AZACYCLIC COMPOUNDS

Abstract: Compounds of formula (I), and salts and prodrugs thereof wherein n is 1, 2 or 3; X represents O or S; Y represents a hydrocarbon chain of 1, 2, 3 or 4 carbon atoms optionally substituted by oxo; R<1> is phenyl optionally substituted by 1, 2 or 3 of C1-6alkyl, C2-6alkenyl, C2-6alkynyl, halo, cyano, nitro, trifluoromethyl, trimethylsilyl, -OR<a>, SR<a>, SOR<a>, SO2R<a>, -NR<a>R<b>, -NR<a>COR<b>, -NR<a>CO2R<b>, -CO2R<a> or -CONR<a>R<b>; R<2> is phenyl, indazolyl, thienyl, furyl, pyridyl, thiazolyl, tetrazolyl, quinolyl, benzhydryl, or benzyl; R<4> and R<5> each independently represent H, halo, C1-6alkyl, oxo, CH2OR<a>, CO2R<a> or CONR<a>R<b>; R<8> represents an optionally substituted aromatic heterocycle; and R<a> and R<b> are H, trifluoromethyl, C1-6alkyl or phenyl optionally substituted by C1-6alkyl, halo or trifluoromethyl; are tachykinin antagonists useful in medecine.

Description: AZACYCLIC COMPOUNDS This invention relates to a class of azacyclic compounds, which are useful as tachykinin antagonists. More particularly, the compounds of the invention comprise an azacyclic ring system substituted by an arylmethyloxy or arylmethylthio moiety. The tachykinins are a group of naturally- occurring peptides found widely distributed throughout mammalian tissues, both within the central nervous system and in the-peripheral nervous and circulatory systems. The structures of three known mammalian tachykinins are as follows: Substance P: Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met-NH-2 Neurokinin A: His-Lys-Thr-Asp-Ser-Phe-Val-Gly-Leu-Met-NH2 Neurokinin B: Asp-Met-His-Asp-Phe-Phe-Val-Gly-Leu-Met-NH 2 For example, substance P is believed inter alia to be involved in the neurotransmission of pain sensations [Otsuka et al, "Role of Substance P as a Sensory Transmitter in Spinal Cord and Sympathetic Ganglia" in 1982 Substance P in the Nervous System, Ciba Foundation Symposium 91, 13-34 (published by Pitman) and Otsuka and Yanagisawa, "Does Substance P Act as a Pain Transmitter?" TIPS (Dec. 1987) 8.506-510], specifically in the transmission of pain in migraine (B.E.B. Sandberg et al, J. Med Chem, (1982) 25 1009; S.L. Shepheard et al.. Br. J. Pharmacol. (1993), 108. 11-12) and in arthritis [Levine et al in Science (1984) 226 547-549]. These peptides have also been implicated in gastrointestinal (GI) disorders and diseases of the GI tract such as inflammatory bowel disease [Mantyh et al in Neuroscience (1988) 25. (3) 817-37 and D. Regoli in "Trends in Cluster Headache" Ed. Sicuteri et al Elsevier Scientific Publishers, Amsterdam (1987) page 85)]. It is also hypothesised that there is a neurogenic mechanism for arthritis in which substance P may play a role [Kidd et al "A Neurogenic Mechanism for Symmetrical Arthritis" in The Lancet, 11 November 1989 and Grδnblad et al "Neuropeptides in Synovium of Patients with Rheumatoid Arthritis and Osteoarthritis" in J. Rheumatol. (1988) 15(12) 1807-10]. Therefore, substance P is believed to be involved in the inflammatory response in diseases such as rheumatoid arthritis and osteoarthritis [0'Byrne et al in Arthritis and Rheumatism (1990) 3J3 1023-8]. Other disease areas where tachykinin antagonists are believed to be useful are allergic conditions [Hamelet et al Can. J. Pharmacol. Physiol. (1988) 66 1361-7], immunoregulation [Lotz et al Science (1988) 2411218-21 and Ki ball et al, J. Immunol. (1988) 141 (10) 3564-9] vasodilation, bronchospasm, reflex or neuronal control of the viscera [Mantyh et al, PNAS (1988) 85 3235-9] and, possibly by arresting or slowing β-amyloid-mediated neurodegenerative changes [Yankner et al Science, (1990) 250. 279-82] in senile dementia of the Alzheimer type, Alzheimer's disease and Down's Syndrome. Substance P may also play a role in demyelinating diseases such as multiple sclerosis and amyotrophic lateral sclerosis [J. Luber-Narod et. al., poster " resented at C.I.N.P. XVIIIth Congress, 28th June- 2nd July, 1992], and in disorders of bladder function such as bladder detrusor hyper-reflexia (Lancet. 16th May, 1992, 1239). It has furthermore been suggested that tachykinins have utility in the following disorders: depression, dysthymic disorders, chronic obstructive airways disease, hypersensitivity disorders such as poison ivy, vasospastic diseases such as angina and Reynauld's disease, fibrosing and collagen diseases such as scleroderma and eosinophillic fascioliasis, reflex sympathetic dystrophy such as shoulder/hand syndrome, addiction disorders such as alcoholism, stress related somatic disorders, neuropathy, neuralgia, disorders related to immune enhancement or suppression such as systemic lupus erythmatosis (European patent application no. 0 436 334), ophthalmic disease such as conjuctivitis, vernal conjunctivitis, and the like, and cutaneous diseases such as contact dermatitis, atropic dermatitis, urticaria, and other eczematoid dermatitis (European patent application no. 0 394 989) and emesis (European patent application no. 0533 280) . In view of their metabolic instability, peptide derivatives are likely to be of limited utility as therapeutic agents. It is for this reason that non- peptide tachykinin antagonists are sought. European patent application no. 0 436 334 discloses 4- to 7-membered azacyclic compounds substituted at the 3-position by a substituted amino moiety. The compounds are said to be tachykinin antagonists. The present invention provides a compound of formula (I) , or a salt or prodrug thereof: (I) wherein n is 1, 2 or 3; X represents O or S; Y represents a hydrocarbon chain of 1, 2, 3 or 4 carbon atoms which may optionally be substituted by oxo; R 1 represents phenyl optionally substituted by l r 2 or 3 groups selected from Ci-galkyl, C2-6 alkenyl, C2-6alkyn l, halo, cyano, nitro, trifluoromethyl, trimethylsilyl, -OR a , SR a , SOR a , S0 2 R a , -NR a R b , -NR a C0R b , -NR a C0 2 R b , -C0 2 R a or -CONR a R b ; R 2 represents aryl selected from phenyl and naphthyl; heteroaryl selected from indazolyl, thienyl, furyl, pyridyl, thiazolyl, tetrazolyl and quinolyl; benzhydryl; or benzyl; wherein each aryl or heteroaryl moiety may be substituted by Cι_βalkyl, Cχ_βalkoxy, halo or trifluoromethyl; R 4 and R 5 may be present on any available carbon atom of the azacyclic ring and each independently represent H, halo, Cι_galkyl, oxo, CH2θR a , Cθ2R a or CONR a R b ; R 8 represents an optionally substituted aromatic heterocycle; and R a and R b each independently represent H, trifluoromethyl, Ci-ealkyl or phenyl optionally substituted by Ci-βalkyl, halo or trifluoromethyl. As used herein, the definition of each expression, when it occurs more than once in any structure, is intended to be independent of its definition elsewhere in the same structure. The alkyl, alkenyl and alkynyl groups referred to with respect to the above formula may represent straight, branched or cyclic groups, or combinations thereof. Thus, for example, suitable alkyl groups include methyl, ethyl, n- or iso-propyl, n-, sec-, iso- or tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, and cycloalkyl-alkyl groups such as cyclopropylmethyl; suitable alkenyl groups include vinyl and allyl; and suitable alkynyl groups include propargyl. The term "halo" as used herein includes fluoro, chloro, bro o and iodo, especially chloro and fluoro. The present invention includes within its scope prodrugs of the compounds of formula (I) above. In general, such prodrugs will be functional derivatives of the compounds of formula (I) which are readily convertible in vivo into the required compound of formula (I) . Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in "Design of Prodrugs", ed. H. Bundgaard, Elsevier, 1985. The compounds according to the invention may exist both as enantiomers and as diastereomers. In particular, the relative orientation of the 2- and 3- substituents on the azacyclic ring may give rise to cis and trans diastereoisomers, of which the cis stereochemistry is preferred. It is to be understood that all such isomers and mixtures thereof are encompassed within the scope of the present invention. Preferably n is 2 or 3, more preferably 3. Preferably X represents O. Suitably Y represents a hydrocarbon chain of 1 or 2 carbon atoms optionally substituted by oxo, such as CH 2 , C=0, CH(CH 3 ), CH 2 (C=0) or (C=0)CH 2 . Preferably Y represents CH2 CH(CH3) or CH2(C=0), more preferably CH2 or CH(CH3) . A particularly preferred subgroup of compounds according to the invention is represented by compounds of formula (I) wherein Y is CH(CH 3 ) . Preferably R 1 represents substituted phenyl. When R 1 is substituted phenyl suitable substituents include nitro, trifluoromethyl, trimethylsilyl, bromo, chloro, fluoro, iodo, cyano, Cι_galkyl such as methyl, ethyl, i-propyl, i-butyl, t-butyl and cyclopropyl, C2-6alkenyl such as vinyl, Ci-galkoxy such as methoxy, ethoxy and i-propoxy, phenoxy, amino, carboxamido and carbonylmethoxy. Preferably R^- represents phenyl substituted by one or more groups selected from C _4alkyl, such as methyl and t-butyl, trifluoromethyl and halo such as iodo, bromo chloro and fluoro. Suitably R 1 represents monosubstituted phenyl, such as 3-substituted phenyl or, preferably, disubstituted phenyl, such as 3,5-disubstituted phenyl. Preferably R 1 represents phenyl substituted at the 3- position by trifluoromethyl or a C^-galkyl group such as t-butyl, or 3,5-disubstituted phenyl wherein the substituents are independently selected from trifluoromethyl, chloro, fluoro, methyl and t-butyl. Preferred values for R 1 include 3,5- bis(trifluoromethyl)phenyl, 3,5-dichlorophenyl, 3-t- butyl-5-methylphenyl, 3-chloro-5-methylphenyl, 3-t-butyl- 5-chlorophenyl, 3-bis(trifluoromethyl)phenyl and 3-t- butylphenyl. Particularly preferred is 3,5- bis(trifluoromethyl)phenyl. Suitably R 2 represents benzhydryl or optionally substituted phenyl, such as phenyl optionally substituted by halo such as fluoro or chloro, preferably in the 3- position. Preferably R 2 represents unsubstituted phenyl or unsubstituted benzhydryl, more preferably unsubstituted phenyl. Suitable values for R 4 and R 5 include H, Ci-galkyl, especially methyl, hydroxymethyl and oxo. The substitutents R 4 and R 5 may be located on any available carbon atom of the azacyclic ring including, except in the case where the substituent R 4 or in question represents oxo, C-2 and C-3. Preferably at least one of R 4 and R 5 represents H. In one preferred group of compounds R 4 and R 5 both represent H. In a further preferred group of compounds one of R and R 5 is H and the other of R 4 and R 5 is methyl, preferably 2-methyl. When R represents a substituted aromatic heterocycle, suitable substituents in the heterocyclic ring include one or more of Ci-βalkyl, Ci-galkoxy, phenyl, oxo, thioxo, halo, trifluoromethyl, NR a R b , NR a C0R b , C0NR a R b , C0 2 R a , SR a , S0 2 R a and CH 2 0R a , where R a and R b are as previously defined. Particular examples of suitable substituents include methyl, methoxy, phenyl, oxo, thioxo, bromo, iodo, NH2 SCH3, CO H2 and cyano. Particularly preferred substituents include oxo and NH2. Suitable values for R 8 include thienyl, furyl, pyrrolyl, pyridyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, oxazolyl, oxadiazolyl, thiadiazolyl, isoxazolyl, quinolyl, isothiazolyl, imidazolyl, benzimidazolyl, benzoxazolyl, benzothiophenyl, benzofuranyl and indolyl, any of which may be substituted. In particular, R 8 may represent optionally substituted thienyl, furyl, pyridyl, triazolyl, tetrazolyl, thiazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, oxazolyl, oxadiazolyl, thiadiazolyl, imidazolyl, benzimidazolyl or benzoxazolyl. In one group of compounds according to the invention R 8 represents optionally substituted pyrrolyl, pyrazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, oxadiazolyl, thiadiazolyl, imidazolyl, benzimidazolyl, benzoxazolyl, benzothiophenyl, benzofuranyl or indolyl. Preferably R 8 represents a substituted or unsubstituted 5- or 6-membered nitrogen containing aromatic heterocycle such as for example oxazolyl, oxadiazolyl, tetrazolyl, thiazolyl, thiadiazolyl, triazolyl, pyrazinyl, pyridyl, pyrimidinyl, pyridazinyl, imidazolyl or triazinyl. More preferably R 8 represents optionally substituted oxazolyl, oxadiazolyl, imidazolyl, thiadiazolyl, triazolyl, pyrazinyl, pyrimidinyl, pyridazinyl or triazinyl, or tetrazolyl substituted by Ci-galkyl, preferably methyl. In one preferred group of compounds according to the invention, R 8 represents substituted or unsubstituted oxadiazolyl, for example, oxadiazolyl substituted by halo, amino, dialkylamino or methyl. More preferably R 8 represents 5-(3-aminooxadiazolyl) . In a further preferred group of compounds according to the invention, R 8 represents substituted or unsubstituted triazolyl, for example, unsubstituted triazolyl or triazolyl subtituted by oxo or thioxo, more preferably, triazolyl substituted by oxo. It will be appreciated that, when the heterocyclic moiety R 8 is substituted by an oxo or thioxo substituent, different tautomeric forms are possible so that the substituent may be represented as =0 or -OH, or =S or -SH, respectively. For the avoidance of doubt, all such tautomeric forms are embraced by the present invention. One subgroup of compounds according to the invention is represented by compounds of formula (IA) , and salts and prodrugs thereof: ("A) wherein n is 1, 2 or 3 and where any carbon atom of ( CH 2)n ma Y be substituted by R 12 and/or R 13 ; X represents 0 or S; R 10 represents phenyl optionally substituted by 1, 2 or 3 groups selected from Ci-galkyl, C2-6 alkenyl, C2-6alkynyl, halo, cyano, nitro, trifluoromethyl, trimethylsilyl, -OR c , SR C , SOR c , S0 2 R c , -NR c R d , -NR c COR d , -NR c C0 2 R d , -C0 2 R c or -CONR c R d ; R ll represents aryl selected from phenyl and naphthyl; heteroaryl selected from indazolyl, thienyl, furyl, pyridyl, thiazolyl, tetrazolyl and quinolyl; benzhydryl; or benzyl; wherein each aryl or heteroaryl moiety may be substituted by Ci-galkoxy, halo or trifluoromethyl; R 12 and R 13 each independently represent H, halo, Cx-ealkyl, oxo, C0 R c or CONR c R d ; R 14 represents C1-4alkyl, optionally substituted by oxo, substituted by an optionally substituted aromatic heterocycle; and R c and R d each independently represent H, Ci-gal l, phenyl optionally substituted by Cι_galkyl or halo or trifluoromethyl. Suitable values for the heterocyclic moiety of R 14 include thienyl, furyl, pyrrolyl, pyridyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, pyrazinyl, pyridazinyl, oxazolyl, oxadiazolyl, thiadiazolyl, ^.soxazolyl, quinolyl, isothiazolyl, imidazolyl, benzimidazolyl, benzoxazolyl, benzothiophenyl, benzofuranyl and indolyl. in one sub-class of compounds of formula (IA) , R c and R d each independently represent H, Cι_galkyl, phenyl or trifluoromethyl. A further subclass of compounds of formula (IA) is represented by compounds wherein n is 2 or 3; R 12 and R 13 each independently represent H, halo, C _galkyl, Cθ2R c or C0NR c R d ; R 14 represents Cι_4alkyl substituted by an optionally substituted 5- or 6-membered aromatic heterocycle; and R c and R d each independently represent H, Cι_galkyl, phenyl or trifluoromethyl. For the compounds of this subclass, suitable values for the heterocyclic moiety of R 14 include thienyl, furyl, pyrrolyl- pyridyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl, oxadiazolyl, thiadiazolyl, isoxazolyl, isothiazolyl and imidazolyl. A preferred sub-class of compounds according to the invention is represented by compounds of formula (IB) , and salts and prodrugs thereof: ,20 (IB) wherein X represents O or S, preferably 0; ~ Y is as defined for formula (I) , preferably Cι_2alkyl optionally substituted by oxo, more preferably CH 2 or CH(CH 3 ) ; R 2 represents phenyl or benzhydryl wherein any of the phenyl rings of the phenyl or benzhydryl moieties may optionally be substituted by halo or trifluoromethyl, preferably unsubstituted phenyl; R 8 is as defined for formula (I) ; and R 20 and R 21 independently represent H, Cι_galkyl, C2-galkenyl, C2-galkynyl, bromo, chloro, fluoro, iodo, cyano, nitro, trifluoromethyl, trimethylsilyl, 0R a , SR a SOR a , S0 2 R a , NR a R b , NR a C0R , NR a C0 2 R b , COR a , C0 2 R a or C0NR a R b , where R a and R b are as previously defined; and z is- 1 or 2. Particular values of R 20 and R 21 include H, methyl, t-butyl, methoxy, i-propoxy, chloro, fluoro, nitro, amino, carbonylmethoxy, carboxamido and trifluoromethyl. Preferably R 20 and R 21 are both other than H, more preferably Cι_galkyl, halo or trifluoromethyl, and are located at the 3- and 5- positions of the phenyl ring. One sub-class of compounds according to the invention are compounds of formula (IB) wherein R 8 is optionally substituted pyrrolyl, pyrazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, imidazolyl, benzimidazolyl, benzoxazolyl, benzothiophenyl, benzofuranyl, indolyl, thiadiazolyl or oxadiazolyl, more preferably oxadiazolyl. A further sub-class of compounds according to the invention are compounds of formula (IB) wherein R is optionally substituted oxadiazolyl, pyridinyl, benzimidazolyl, tetrazolyl, thiazolyl, furyl, thienyl, triazolyl, thiadiazolyl, benzoxazolyl, oxazolyl, pyrazinyl, pyridazinyl, triazinyl, pyrimidinyl or imidazolyl. A particularly preferred group of compounds according to the invention are compounds of formula (Ia) wherein R 8 is optionally substituted triazolyl, especially triazole substituted by oxo. For use in medicine, the salts of the compounds of formula (I) will be pharmaceutically acceptable salts. Other salts may, however, be useful in the preparation of the compounds according to the invention (such as the dibenzoyltartrate salts) 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, oxalic acid, fumaric acid, maleic acid, succinic acid, acetic acid, citric acid, tartaric acid, carbonic acid, phosphoric acid or p-toluenesulphonic acid. Salts of amine groups may also comprise quaternary ammonium salts in which the amino nitrogen atom carries a suitable organic group such as an alkyl, alkenyl, alkynyl or aralkyl moiety. Furthermore, where the compounds of the invention carry an acidic moiety, suitable pharmaceutically acceptable salts thereof may include metal salts such as alkali metal salts, e.g. sodium or potassium salts; and alkaline earth metal salts, e.g. calcium or magnesium salts. Preferred salts of the compounds according to the invention include the hydrochloride and p- toluenesulphonic acid salts. 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, solutions or suspensions, or suppositories, for oral, parenteral or rectal administration, or administration by inhalation or insufflation. The invention further provides a process for the preparation of a pharmaceutical composition comprising a compound of formula (I) , or a salt or prodrug thereof, and a pharmaceutically acceptable carrier, which process comprises bringing a compound of formula (I) , or a salt or prodrug thereof into association with a pharmaceutically acceptable carrier. 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 non¬ toxic 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.. Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders. The liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as set out above. Preferably the compositions are adminsitered by the oral or nasal respiratory route for local or systemic effect. Compositions in preferably- sterile pharmaceutically acceptable solvents may be nebulised by use of inert gases. Nebulised solutions may be breathed directly from the nebulising device or the nebulising device may be attached to a face mask, tent or intermittent positive pressure breathing machine. Solution, suspension or powder compositions may be administered, preferably orally or nasally, from devices which deliver the formulation in an appropriate manner. The compounds of formula (I) are of value in the treatment of a wide variety of clinical conditions which are characterised by the presence of an excess of tachykinin, in particular substance P, activity. These may include disorders of the central nervous system such as anxiety, depression, psychosis and schizophrenia; neurodegenerative disorders such as dementia, including senile dementia of the Alzheimer type, Alzheimer's disease and Down's syndrome; demyelinating diseases such as multiple sclerosis (MS) and amyotropic lateral sclerosis (ALS; Lou Gehrig's disease) and other neuropathological disorders such as peripheral neuropathy, for example, diabetic or chemotherapy-induced neuropathy, and postherpetic and other neuralgias; respiratory diseases such as chronic obstructive airways disease, bronchopneumonia, bronchospasm and asthma; inflammatory diseases such as inflammatory bowel disease, psoriasis, fibrositis, osteoarthritis and rheumatoid arthritis; allergies such as eczema and rhinitis; hypersensitivity disorders such as poison ivy; ophthalmic diseases such as conjunctivitis, vernal conjunctivitis, and the like; cutaneous diseases such as contact dermatitis, atropic dermatitis, urticaria, and other eczematoid dermatitis; addiction disorders such as alcoholism; stress related somatic disorders; reflex sympathetic dystrophy such as shoulder/hand syndrome; dysthymic disorders; adverse immunological reactions such as rejection of transplanted tissues and disorders related to immune enhancement or suppression such as systemic lupus erythematosis; gastrointestinal (GI) disorders and diseases of the GI tract such as disorders associated with the neuronal control of viscera such as ulcerative colitis, Crohn's disease and incontinence; ernesis, including acute, delayed and anticipatory emesis, for example, induced by chemotherapy, radiation, toxins, pregnancy, vestibular disorders, surgery, migraine and variations in intercranial pressure; disorders of bladder function such as bladder detrusor hyper-reflexia; fibrosing and collagen diseases such as scleroderma and eosinophilic fascioliasis; disorders of blood flow caused by vasodilation and vasospastic diseases such as angina, migraine and Reynaud's disease; and pain or nociception, for example, that attributable to or associated with any of the foregoing conditions, especially the transmission of pain in migraine. For example, the compounds of formula (I) may suitably be used in the treatment of disorders of the central nervous system such as anxiety, psychosis and schizophrenia; neurodegenerative disorders such as senile dementia of the Alzheimer type, Alzheimer's disease and Down's syndrome; respiratory diseases, particularly those associated with excess mucus secretion, such as chronic obstructive airways disease, bronchopneumonia, chronic bronchitis, cystic fibrosis and asthma, and bronchospasm; inflammatory diseases such as inflammatory bowel disease, osteoarthritis and rheumatoid arthritis; adverse immunological reactions such as rejection of transplanted tissues; gastrointestinal (GI) disorders and diseases of the GI tract such as disorders associated with the neuronal control of viscera such as ulcerative colitis, Crohn's disease and incontinence; disorders of blood flow caused by vasodilation; and pain or nociception, for example, that attributable to or associated with any of the foregoing conditions or the transmission of pain in migraine. The compounds of formula (I) are particularly useful in the treatment of pain or nociception and/or inflammation and disorders associated therewith such as, for example, neuropathy, such as diabetic and chemotherapy-induced neuropathy, postherpetic and other neuralgias, asthma, osteroarthritis, rheumatoid arthritis and especially migraine. - The present invention further provides a compound of formula (I) for use in therapy. According to a further or alternative aspect, the present invention provides a compound of formula (I) for use in the manufacture of a medicament for the treatment of physiological disorders associated with an excess of tachykinins, especially substance P. The present invention also provides a method for the treatment or prevention of physiological disorders associated with an excess of tachykinins, especially substance P, which method comprises administration to a patient in need thereof of a tachykinin reducing amount of a compound of formula (I) or a composition comprising a compound of formula (I) . For the treatment of certain conditions it may be desirable to employ a compound according to the present invention in conjunction with another pharmacologically active agent. For example, for the treatment of respiratory diseases such as asthma, a compound of formula (I) may be used in conjunction with a bronchodilator, such as a -adrenergic receptor antagonist or tachykinin antagonist which acts at NK-2 receptors. The compound of formula (I) and the bronchodilator may be administered to a patient simultaneously, sequentially or in combination. The present invention accordingly provides a method for the treatment of a respiratory disease, such as asthma, which method comprises administration to a patient in need thereof of an effective amount of a compound of formula (I) and an effective amount of a bronchodilator. The present invention also provides a composition comprising a compound of formula (I) , a bronchodilator, and a pharmaceutically acceptable carrier. In the treatment of the conditions associated with an excess of tachykinins, a suitable dosage level is about 0.001 to 50 mg/kg per day, in particular about 0.01 to about 25 mg/kg, such as from about 0.05 to about 10 mg/kg of a compound of formula (I) per day. For example, in the treatment of conditions involving the neurotransmission of pain sensations, a suitable dosage level is about 0.001 to 25 mg/kg per day, preferably about 0.005 to 10 mg/kg per day, and especially about 0.005 to 5 mg/kg per day. The compounds may be administered on a regimen of 1 to 4 times per day, preferably once or twice per day. According to one general process (A) , the compounds according to the invention may be prepared by a process which comprises reacting a compound of formula (II) : (ID wherein R 1 , R 2 , R 4 , R 5 , X and n are as defined for formula (I) above, with a reagent suitable to introduce the group Y-R 8 , for example, a halide or acyl halide, or corresponding mesylate or tosylate, of formula R 8 -Y-L, where L represents halo, such as chloro, bromo or iodo, methylsulphonate or ~ - toluenesulphonate,or any other suitable leaving group, in the presence of a base. Suitable bases of use in the reaction include inorganic bases such as alkali metal carbonates, for example, potassium carbonate. Conveniently the reaction is effected in a suitable organic solvent, for example, dimethylformamide. According to a second process (B) , compounds of formula (I) wherein R 8 represents 5-oxadiazolyl may be prepared by reaction of a compound of formula (III) with a compound of formula (IV) : ( I I I ) ( I V ) wherein R 1 , R 2 , R 4 , R 5 , X, Y and n are as defined for formula (I) , R 30 represents an alkyl group and R 31 represents H or a suitable substituent such as Cι_galkyl, Cx- alkoxy, halo, NR a R b or NR a COR b , where R a and R b are as previously defined, in the presence of a base. Suitable bases of use in the reaction include alkali metals, such as, for example, sodium, and alkali metal hydrides, such as, for example, sodium hydride. The reaction is conveniently effected in a suitable organic solvent. Which solvents will be appropriate will depend on the nature of the base used. For example, where the base used is an alkali metal, suitable solvents will include alcohols, for example, ethanol, whereas where the base used is an alkali hydride, suitable solvents will include ethers, for example, tetrahydrofuran. Preferably the reaction is conducted at elevated temperature, such as the reflux temperature of the chosen solvent. According to a further process, (C) , compounds of formula (I) wherein R 8 represents tetrazolyl may be prepared from intermediates of formula (V) : (V) wherein R 1 , R 2 , R 4 , R 5 , X,. Y and n are as defined for formula (I) by treatment with an alkali metal azide, such as sodium azide. The reaction is conveniently effected in a high boiling organic solvent, such as, for example, N-methylpyrrolidinone. According to a further process, (D) , compounds of formula (I) wherein R 8 represents thiazolyl may be prepared from intermediates of formula (VI) : (VI) wherein R 1 , R 2 , R 4 , R 5 , X, Y and n are as defined for formula (I) , by reaction with a compound of formula Hal-CH2C(0)-R 60 , where Hal represents halo, such as bromo, chloro or iodo, and R 60 represents H or a suitable substituent such as Cχ.galkyl. The reaction is conveniently effected in a suitable organic solvent, such as a ketone, for example, acetone, or an alcohol, for example, methanol, or a mixture of solvents, preferably at elevated temperature, such as the reflux temperature of the chosen solvent. According to a futher process, (E) , compounds of formula (I) wherein R 8 represents thioxotriazolyl may be prepared from intermediates of formula (VII) (VI I) wherein R 1 , R 2 , R 4 , R 5 , X, Y and n are as defined for formula (I) , by reaction with a compound of formula R 61 NCS, wherein R 61 represents H or a suitable substituent such as C^-galkyl, in the presence of a base. Suitable bases of use in the reaction include organic bases such as, for example, 1,8- diazabicyclo[5.4.0]undec-7-ene (DBU) . The reaction is conveniently effected in a suitable orgainc solvent, such as alcohol, e.g. butanol. According to a further process, (F) , compounds of formula (I) wherein R 8 represents unsubstituted or substituted triazolyl may be prepared by reaction of intermediates of formula (II) with a compound of formula (VIII) : l (VIM) wherein Y and Hal are as previously defined and R 18 is H or a group suitable as a substituent of the triazole ring, or convertible to such a group under the reaction conditions, in the presence of a base. Suitable bases of use in the reaction include alkali metal carbonates, such as, for example, potassium carbonate. Suitably R 18 represents H, OCH3 (which is converted to an oxo substituent under the reaction conditions) or CONH2. The reaction is conveniently effected in an anhydrous organic solvent, such as, for example, anhydrous dimethylformamide, preferably at elevated temperature, such as about 140 β C. According to a further process, -(G) , compounds of formula (I) wherein R 8 represents substituted or unsubstituted 1,3,5-triazine may be prepared by reaction of intermediates of formula (IX) : (IX) wherein R 1 , R 2 , R 4 , R 5 , X, Y and n are as defined for formula (I), with substituted or unsubstituted 1,3,5- triazine. The reaction is conveniently effected in a suitable organic solvent, such as acetronitrile, at elevated temperature, such as 80-90 β C, preferably about 82'C. According to a further process, (H) , compounds of formula (I) wherein R represents substituted or unsubstituted 1,2,5-triazine may be prepared by reaction of an intermediate of formula (X) with a dicarbonyl compound of formula (XI) : (X) (XI) wherein R 1 , R 2 , R 4 , R 5 , X, Y and n are as defined for formula (I) and R 35 and R 36 each independently represnt H or a suitable substituent such as Cι_galkyl, e.g. methyl. The reaction is conveniently effected in a suitable organic solvent, such as an ether, e.g. tetrahydrofuran, conveniently at ambient temperature. Further details of suitable procedures will be found in the accompanying Examples. Compounds of formula (VIII) may be prepared as described in J. Med. Chem. 27. (1984), 849. Compounds of formula (I) may also be prepared from other compounds of formula (I) using suitable interconversion procedures. For example, compounds of formula (I) wherein Y represents C^_4alkyl substituted by an aromatic heterocycle may be prepared from compounds of formula (I) wherein Y represents C1-.4alkyl substituted by oxo by reduction, for example, using borane. Suitable interconversion procedures are described in the accompanying Examples, or will be readily apparent to those skilled in the art. Intermediates of formula (III) may be prepared from intermediates of formula (II) by reaction with a compound of formula Hal-Y-Cθ2R 30 , where Hal represents halo such as chloro, bromo or iodo and R ° and Y are as above defined, in the presence of a base. Suitable bases include tertiary amines, for example, triethylamine. Conveniently the reaction is effected in a suitable organic solvent, such as an ether, for example, tetrahydrofuran, at elevated temperature, such as the reflux temperature of the solvent. Intermediates of formula (IV) are commercially available or may be prepared from commercially available materials by conventional procedures well-known to those skilled in the art. Intermediates of formula (II) may be prepared as described in published European patent application no. 0 528 495. Intermediates of formula (V) may be prepared from intermediates of formula (II) by reaction with a compound of formula Hal-Y-CN, wherein Hal is halo such as bromo, chloro or iodo and Y is as previously defined. Intermediates of formula (VI) may be prepared from intermediates of formula (V) by treatment with an alkylthioamide, such as, for example, thioacetamide. Intermediates of formula (VII) may be prepared from intermediates of formula (III) by treatment with hydrazine. The reaction is conveniently effected in a suitable organic solvent, such as an alcohol, for example, ethanol, at elevated temperature. Intermediates of formula (IX) may be prepared from intermediates of formula (II) by reaction with a compound of formula Hal-Y-C(NH)NH2 where Hal and Y are as previously defined. Intermediates of formula (X) may be prepared from intermediates of formula (II) by reaction with a compound of formula Hal-Y-C(NH)NHNH-Boc, wherein Hal and Y are as previously defined and Boc stands for t-butoxycarbonyl, followed by deprotection under acidic conditions. Compounds of formula (XI) are commercially available or may be prepared from commercially available compounds by known methods. Where the above-described process for the preparation of the compounds according to the invention gives rise to mixtures of stereoisomers these isomers may, if desired, be separated, suitably by conventional techniques such as preparative chromatography. The novel compounds may be prepared in racemic form, or individual enantiomers may be prepared either by enantiospecific synthesis or by resolution. For example, any suitable intermediates may be resolved into their component enantiomers by standard techniques, such as the formation of diastereomeric esters or amides, followed by chromatographic separation or separation by fractional crystallization and removal of the chiral auxiliary. The diastereomeric intermediates can then be used to prepare optically pure compounds of formula (I) . 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 and P.G.M. Wuts, Protective Groups in Orσanic 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 substance P antagonising activity of the compounds described herein was evaluated using the human NK1R assay described in published European patent application no. 0 528 495. The method essentially involves determining the concentration of the test compound required to reduce by 50% the amount of radiolabelled substance P binding to human NK1R, thereby affording an IC50 value for the test compound. The compounds of Examples 1-10, for example, were found to have IC50 . values less than 500nM. DESCRIPTION 1: s-3-((3.5-Bisf1-rifluoromethyl)phenvDmethv^ oxv;-2-phenvh)iperidine hydrochloride salt a) A solution of methyl 4-nitrobutyrate (23g) and benzaldehyde (16ml) in acetic acid (39ml) containing ammonium acetate (12.12g) was heated at reflux under nitrogen for 2h. The reaction mixture was cooled to 5°C, whereby a pale-yellow solid crystallised- This was isolated by filtration, then dissolved in dichloromethane, washed cautiously with saturated aqueous sodium bicarbonate solution (2 x), then dried (MgS0 4 ) and concentrated to leave a yellow solid. Recrystallisation from ethyl acetate provided 5-nitro-2-oxo-6-phenylpiperidine (12.5g) as a crystalline, white solid, H NMR (CDC1 3 ) d 7.46-7.26 (m), 6.0 (br s), 5.24 (dd, J = 1.4, 7.0Hz), 4.70 (m), 2.70-2.50 (m), 2.38-2.24 (m). b) Potassium f-butoxide (1.68g) was added to a solution of 5-nitro-2-oxo-6-phenylpiperidine (3g) in a mixture of dichloromethane (50ml) and methanol (50ml) and the mixture was cooled to -78°C under nitrogen. Ozone was bubbled through the solution for 3h. A yellow-green solution resulted, and TLC indicated no starting material remained. The reaction mixture was purged with oxygen for 5 min to remove excess ozone, then dimeti-iylsulfide (7ml) was added and the reaction mixture was allowed to warm to 23°C. The solvent was removed in vacuo, and the residue was partitioned between dichloromethane and water. The layers were separated, and the aqueous phase was extracted twice with dichloromethane. The combined organic extracts were washed with brine, then dried and concentrated to leave a yellow solid. This crude material was slurried in dry tetrahydrofuran and added to lithiu aluminium hydride (1M in THF, 50ml) then heated at reflux for 12h. After cooling to 23°C, the reaction mixture was quenched by the cautious addition of water (dropwise) under nitrogen, then 2M sodium hydroxide. The mixture was filtered through a pad of Hyflo, the filtrate was washed with brine, then dried (JLβO-) and concentrated to leave a yellow sohd. Purification by sihca-gel chromatography (CH 2 Cl 2 MeOH/NHg 97:3:1 then 95:5) provided 3-hvdroxy- 2-phenylpiperidine as a £a 4:1 mixture of Sr and iαms-isomers respectively. H NMR (CDC1 3 ) 7.44-7.20 (m), 3.84 (2), 3.76 (s), 3.54 (m), 3.4 (s), 3.3 (d, J = 8Hz), 3.26 (m), 3.04 (m) 2.78 (ddd, J = 2.9, 11.9, 11.9Hz), 2.70 (ddd, J = 2.9, 11.9, 11.9Hz), 2.18-1.78 (m), 1.48 (m). MS (El) m/z 177 (M+). c) Di-έ-butyldicarbonate (1.36g) was added to a solution of 3-hydroxy-2-phenylpiperidine (lg) in dichloromethane (8ml) under nitrogen and the mixture stirred at 23°C for 3h. The solvent was removed in vacuo, and the residue purified by silica-gel chromatography (CH 2 CyMeOH/NH 3 97:3:0.5) to provide cis- and *ran.<?-l-^hutvloxvcarbonvl-3-hvdroxv-2- phenylpiperidine (1.4g) as a clear, viscous oil. X H NMR (CDC1 3 ) d 7.50-7.42 (m), 7.40-7.14 (m), 5.36 (d, J = 5.6Hz), 4.50 (m), 4.44 (m), 4.12-3.92 (m), 3.02 (ddd, J = 3.0, 12.5, 12.5Hz), 2.87 (ddd, J = 3.0, 12.5, 12.5Hz), 1.88-1.66 (m), 1.46 (s), 1.36 (s). d) To a cooled (0°C) solution of l-i-butyloxycarbonyl-3- hydroxy-2-phenylpiperidine (1.4g) in dry dimethylformamide (5ml) was added sodium hydride (80% dispersion in mineral oil; 182mg). The cooling bath was removed and the reaction mixture stirred at 23°C for 30 min. A solution of 3,5- bis(trifluoromethyl)benzyl bromide (1.87g) in dry dimethylformamide (1ml) was added and stirring was continued for 2h at room temperature. The mixture was diluted with water (100ml) and extracted with ethyl acetate (3 x 40ml). The combined organic extracts were washed with brine (1 x 30ml), dried (MgSO 4 ) and evaporated to yield a pale yellow oil. Purification by chromatography on silica using gradient elution of hexane in ethyl acetate (9:1 - 4:1) afforded the product czs-l-f-butvloxvcarbonvl-3-f(3.5-bis(trifluoromethvDphenvD methyloxy)-2-phenylpiperidine (350mg) as an oil. X H NMR (250MHz, CDC1 3 ) d 7.77 (1H, s, ArH), 7.71 (2H, s, ArH), 7.53-7.57 (2H, m, ArH), 7.2-7.4 (3H, m, ArH), 5.70 (1H, br d, app. J = 7.0Hz, NCHPh), 4.73 (2H, brs, OCH 2 ), 3.84-3.98 (2H, m, NCHCHO + NCHH), 2.77 (1H, ddd, J = 13.0, 13.0, 3.0Hz), NCHH), 2.00 (2H, mc, CH 2 ), 1.6-1.8 (2H, m, CH 2 ), 1.40 (9H, s, C(CH 3 ) 3 ). e) Trifluoroacetic acid (3ml) was added to the product of (d) above (800mg) under nitrogen and the resulting solution was stirred for lh. Excess trifluoroacetic acid was removed in vacuo and the residue was partitioned between 2M sodium hydroxide and dichloromethane. The organic phase was washed with brine, dried (MgSO 4 ) and evaporated to afford a colourless oil. Purification on silica (dichloromethane in methanol, 98:2 - 95:5) afforded the product cιs-3-((3,5-bis(trifluoromethyl)phenyl) methyloxy-2-phenylpiperidine (360mg) as a colourless oilr Η NMR (360MHz, CDC1 3 ) d 7.78 (1H, s, ArH), 7.44 (2H, s, ArH), 7.18-7.38 (5H, s, ArH), 4.52 (1H, d, J = 12.5Hz, OCHH), 4.13 (1H, d, J =- 12.5Hz, OCHH), 3.84 (1H, d, J = 1.0Hz, NCHPh), 3.68 (1H, d, J = 1.5Hz), 3.28 (1H, m, NCHCHO), 2.84 (1H, ddd, J = 3.0, 12.5, 12.5Hz, NCHH), 2.20 (1H, mc, NCHH), 1.8-1.98 (2H, m, CH 2 ), 1.64-1.78 (1H, m, CHH), 1.50-1.58 (1H, m, CHH); MS m/z 404 ((M+l) + , 90%). The oil was dissolved in ether to which was added excess ethereal hydrogen chloride. Upon standing a white solid crystallised. This was filtered and recrystalhsed -from ethyl acetate-methanol to afford the title compound as white crystals: mp 200-203°C. Η NMR (360MHz, DMSO) d 7.95 (1H, s, ArH), 7.81 (2H, s, ArH), 7.37-7.47 (5H, m, ArH), 4.78 (1H, d, J = 13.0Hz, OCHH), 4.56 (1H, s, NCHPh), 4.32 (1H, d, J = 13.0Hz, OCHH), 3.96 (1H, s, NCHCHO), 3.10 (1H, t, J = 13.0Hz, NCHH), 2.23 (1H, d, J = 13.0Hz, NCHH), 1.64-2.00 (4H, m, CH 2 x 2); MS (CI + ) m/z 404 ((M+l) + , 90%); Found: C, 54.08; H, 4.47; N, 3.13. Calcd. for C 20 H 20 F 6 NOC1.0.25H 2 O: C, 54.06; H, 4.65; N, 3.15%. DESCRTPTTON 2: (2R*.3R* 3-f.3.5-Bis(trifluoromethyl)phenyl methvloxv.-l-(carbomethoxv)methvl-2-phenvlpiperidine cis-3-((3,5-Bis(trifluoromethyl)phenyl)methyloxy)-2-pheny lpiperidine hydrochloride (Description 1, lg) was Uberated from the hydrochloride salt by partitioning between ethyl acetate and 2M sodium hydroxide. The organic phase was washed successively with water, saturated brine, dried (MgS0 4 ) and evaporated in vacuo. To a solution of the residual oil in tetrahydrofuran (20ml) was added triethylamine (0.4ml) and methyl bromoacetate (400mg) and the solution was heated at reflux under an atmosphere of nitrogen for 16h. To the cooled solution was added ethyl acetate and water and the organic phase washed further with water and dried (MgSO 4 ). After the solvent had been removed in vacuo the residue was chromatographed on silica gel eluting with ethyl acetate/petroleum ether (3:10). The product was recrystallised from diethyl ether/petroleum ether to give the title compound: mp 81-83°C. Found: C, 57.35; H, 4.98; N, 2.84; requires C, 57.71; H, 4.86; N, 2.93%. MS DESCRTPTTON 3: f+V(2S^SVcM-3-ff3.B-BiR(trifluoromethvl ' ) phenylιmethyloxy)-2- phenvlpiperidine hydrochloride salt a) The mixture of cis- and frans-isomers of 3-hydroxy-2- phenylpiperidine (Description 1, (2b)) and 4-toluenesulfonic acid monohydrate was crystalhzed from methanol/ethyl acetate to give cis-3-hydroxy-2-phenylpiperidimum tosylate: mp 266-267°C. b) The tosylate salt (Description 3(a) above) was dissolved in a mixture of ethyl acetate and 10% aqueous Na 2 C0 3 with warming. The organic phase was washed with saturated brine, dried (I^C0 3 ) and evaporated to give crystalline cts-3-hvdroxy-2-phenylpiperidine. mp 110-110.5°C. c) eis-3-fiydroxy-2-phenylpiperidine (Description 3b) and (-)dibenzoyltartrate were dissolved in methanol and crystalhzed by addition of ethyl acetate. The sohd was recrystaHised fro hot methanol to give the hemi dibenzoyltartrate sg t: mp 223-224°C. This was liberated from the salt as described above to give the single enantiomer (+)-cis-3-hydroxy-2- phenylpiperidine, mp 93-95°C. [aF D = +98.5° (c=l, MeOH). The mother Hquors were converted to the free base as described in Description 3b and crystallization using (+)dibenzoyltartrate in an analogous manner to that described above gave (-)-3-hvdroxy-2-phenylpiperidine. mp 93-95°C. [aP D a -97.2° (c=l, MeOH). d) (+)-cis-3-Hydroxy-2-phenylpiperidine was reacted according to the procedure detailed in Description lc-e to give (+)-cJs-3-((3,5-bis(trifluoromethyl)phenyl)methyloxy-2- phenylpiperidine hydrochloride as a crystalline solid: mp 215-216°C. [a] D = +87.3° (c=l, MeOH). NMR (360MHz, DMSO-d 6 ) d 7.95 (1H, s, ArH), 7.81 (1H, s, ArH), 7.47 (2H, m, ArH), 7.37 (3H, m, ArH), 4.78 (1H, d, J = 13.0Hz, OCHH), 4.56 (1H, s, NCHPh), 4.32 (1H, d, J = 13.0Hz, OCHH), 3.96 (1H, s, NCHCHO), 3.10 (1H, t, J = 13.0Hz, NCHH), 2.23 (1H, d, J = 13.0Hz, NCHH), 2.00-1.64 (4H, m, CH 2 x 2); MS (CI + ) m/z 404 (M+l + , 90%); Found: C, 54.52; H, 4.60; N, 3.11. Calcd. for C 20 H 19 F 6 NO.HC1: C, 54.62; H, 4.58; N, 3.18%. DESCRIPTION 4 (t)-(gS,3S)- -((3,5-Pis(triflμorom9thγl) phenvnmethvloxv -l-(carbomethoxv methvl-2-phenvlpiperidine The title compound was prepared from (+)-cis-3-((3,5-bis (trifluoromethyl)phenyl)methyloxy)-2-phenylpiperidine (Description 3) using the procedure detailed in Description 2: mp 60-70°C. [a] D = +132.3° (c=l, MeOH). Η NMR (360MHz, CDClg) d 1.57-1.63 (3H, m, CH 2 + CHH), 2.04-2.17 (2H, m, CHH, CHHN), 3.07-3.10 (1H, m, NCHCHO), 3.20 (1H, d, J = 17.0Hz, NCHHC0 2 CH 3 ), 3.31 (1H, d, J = 17.0Hz, NCHH C0 2 CH 3 ), 3.58 (3H, s, CH 3 ), 3.93 (1H, s, NCHPh), 4.07 (1H, d, J = 12.0Hz, OCHH), 4.49 (1H, d, J = 12.0Hz, OCHH), 7.28-7.34 (3H, m, ArH), 7.43-7.45 (2H, m, ArH), 7.54 (2H, s, ArH), 7.71 (1H, s, ArH). MS (CI + ) m/z 476 (M+l + , 100%). Found: C, 58.31; H, 4.90; N, 2.94. Calcd. for C^Jzϊ^ ^Os. 58.11; H, 4.88; N, 2.95%. DESCRIPTION 5: (2R*.3R*)-3-((3.S-Bisftrifluorom e thyl,phenyl) methvloxvVl-(cvanomethvl)-2-phenvlpiperidinium hydrochloride The compound of Description 1 (5g), potassium carbonate (1.7g) and bromoacetonitrile (0.87ml) were suspended in dimethylformamide (15ml) and the mixture was stirred tinder nitrogen at 60°C for 3 h. The mixture was cooled, diluted with water (200ml) and extracted with ethyl acetate (2 x 50ml). The organic extracts were washed with brine, dried (MgS0 4 ) and evaporated, affording a brown oil. This was purified on silica using ethyl acetate in petrol (10%) as eluant. This afforded the product as a colourless oil. The hydrochloride salt was prepared by dissolution in ethereal hydrogen chloride and the salt was recrystallised from ether-hexane: mp 133-134°C. Η NMR (360MHz, CDC1 3 ) d 1.75 (2H, mc, CHH), 1.90 (2H, mc, CHH), 2.31 (1H, mc, CHH), 2.71 (1H, mc, CHH), 3.19 (1H, mc, CHHN), 3.72 (1H, mc, CHHN), 3.81 (1H, d, J = 17.5Hz, NCHHCN), 3.86 (1H, s, CHO), 4.02 (1H, d, J = 17.5Hz, NCHHCN), 4.09 (1H, s, CHPh), 4.35 (1H, d, J = 13.0Hz, OCHH), 4.73 (1H, d, J = 13.0Hz, OCHH), 7.4 (3H, mc, ArH), 7.69-7.73 (5H, m, ArH); MS (CI + ) m z 443 (M++1, 30%). Found: C, 54.87; H, 4.30; N, 5.66. Calcd. for C^H^N- j O-HCl : C, 55.18; H, 4.42; N, 5.85%. DESCRIPTION fi: (2R*-3R* -3-rr3.5-Bi S (trifluoromethv phenvl methyloxy)-2-phenyl-l-rthiocarhnτaτnidomethyl)piperidine The compound of Description 5 (lg) was dissolved in dimethylformamide (anhydrous, 10ml) and the solution was saturated with dry hydrogen chloride gas. The reaction was heated to 100°C under nitrogen and thioacetamide (0.34g) was added; this mixture was allowed to stir at 100°C for 3h. Dimethyfformamide was removed in vacuo. The residue was extracted with ethyl acetate and the organic layer was washed with aqueous sodium bicarbonate, brine, dried (MgS0 4 ) and concentrated in vacuo to afford a brown oil. This was purified on silica using a gradient elution of ethyl acetate in petrol (10-50%). The product was further purified by recrystalhsation from ethyl acetate-petrol: mp 164-166°C; Η NMR (360MHz, CDC1 3 ) d 1.56-1.70 (2H, m, CH 2 ), 1.96-2.10 (1H, m, CHH), 2.15-2.32 (2H, m, CHHN + CHH), 2.98-3.06 (1H, bd, NCHH), - 3.09 (1H, d, J = 18.0Hz, CHHSNH 2 ), 3.50 (1H, d, J = 18.0Hz, NCHHCSNH 2 ), 3.50 (IH, s, CHO), 3.60 (IH, s, NCHPh), 4.04 (IH, d, J = 12.0Hz, OCHHAr), 4.47 (IH, d, J = 12.0Hz, OCHHAr), 7.26-7.36 (5H, m, CH£ ), 7.53 (2H, s, Ar-H), 7.75 (H, s, Ar-H), 7.61 (IH, bs, NHH), 8.99 (IH, bs, NHH); MS (CI + ) m/z 477 (M + +l, 15%); Found: C, 55.09; H, 4.58; N, 5.97. Calc for C 22 H 22 F 6 N 2 OS : C, 55.46; H, 4.65; N, 5.88. DESCRTPTTON 7: (2R*.3R*V3-((3.5-Bi R (triflιιorom 6 thvDph 6 nvl) methyloxy)-l-(carboxyhvdrazidomethyl)-2-phenylpiperidinium hydrQchloride Hydrazine hydrate (3.0ml) was added to a solution of the compound of Description 2 (2.95g) in ethanol (80ml). The solution was heated at reflux for 18h after which the ethanol was removed in vacuo. The residue was extracted into ethyl acetate and the organic layer was washed with brine, dried (MgS0 4 ) and concentrated to give the title compound (2.79g). This was dissolved in methanol (5ml) and a methanolic solution of hydrogen chloride was added. Methanol was removed in vacuo and the salt was recrystallised from diethyl ether to give the hydrochloride salt. Η NMR (360MHz, DMSO) d 1.77-1.93 (2H, m, CH 2 ), 2.08-2.21 (IH, m, CH 2 ), 2.22-2.35 (IH, m, CH 2 ), 3.56 (IH, d, NCHHCH 2 ), 3.64 (IH, d, J = 16.5Hz, NCHHCO), 3.77 (IH, d, NCHHCH 2 ), 3.92 (IH, d, J = 16.5Hz, NCHHCO), 3.96 (IH, brs, CHO), 4.37 (IH, d, J = 13.0Hz, OCHH), 4.83 (IH, d, J = 13.0Hz, OCHH), 4.95 (IH, s, CHPh), 7.36-7.46 (3H, m, ArH), 7.53-7.62 (2H, brs, ArH), 7.95 (2H, s, ArH), 7.97 (IH, s, ArH); MS (CI) + m z 475. DESCRIPTION 8: (2S.3S).3-((3.5-Bisftriflπoromethy1 nheττyl methyloxy)-l-(carboxyhvdrazidomethyl)-2-phenylpiperidinium hydrochloride The title compound was prepared according to the procedure outlined in Description 7 using the compound of Description 4 as a starting material. l H NMR (360MHz, DMSO) d 1.77-1.93 (2H, m, CH 2 ), 2.08-2.21 (IH, m, CH 2 ), 2.22-2.35 (IH, m, CH 2 ), 3.56 (IH, d, NCHHCH 2 ), 3.64 (IH, d, J = 16.5Hz, NCHHCO), 3.77 (IH, d, NCHHCH 2 ), 3.92 (IH, d, J = 16.5Hz, NCHHCO), 3.96 (IH, brs, CHO), 4.37 (IH, d, J = 13.0Hz, OCHH), 4.83 (IH, d, J = 13.0Hz, OCHH), 4.95 (IH, s, CHPh), 7.36-7.46 (3H, m, ArH), 7.53-7.62 (2H, brs, ArH), 7.95 (2H, s, ArH), 7.97 (IH, s, ArH); MS (CD + m/z 475. DESCRIPTION 9: (2S.3S)-3-((3.5-Bi S (triflnoromethvnphenvl) methyloxyVl- (cvanomethylV2-phenvIpiperidine The title compound was prepared from the reaction of bromoacetonitrile and the compound of Description 3 according to the procedure detailed in Description 5. Purification by chromatography on silica using 10% hexane in ethyl acetate afforded the product as a colourless oil. Η NMR (360MHz, CDC1 3 ) d 1.75 (2H, mc, CHaCHgN), 2.14 (2H, mc, CH 2 CH 2 N), 2.63-2.74 (IH, m, CHHN), 2.96-3.06 (IH, m, CHHN), 3.35 (IH, d, J=17.0Hz, CHHCN), 3.48 (IH, d, J=2.0Hz, CHO), 3.55 (IH, d, J=17.0Hz, CHHN), 3.64 (IH, d, J=2.0Hz, CHPh), 4.07 (IH, d, J=12.0Hz, OCHH), 4.52 (IH, d, J=12.0Hz, OCHH), 7.28-7.38 (3H, m, ArH), 7.4-7.48 (2H, m, ArH), 7.56 (2H, m ArH), 7.73 (lH, m, ArH). DESCRIPTION 10: (2S.3S -3-((3-^ButvI-5-methylphenyl) methvloxvV2-phenvlpiperidinβ This compound was prepared from the compound of Description 3c and 3-£-butyl-5-methylbenzyl bromide, following the procedure described in Descriptions lc-e. mp 180-182°C. MS (CI + ) m/z 338 (M + +l, 100%). Found: C, 73.81; H, 8.63; N, 3.74. Calcd. for C 23 H 31 N0.HC1: C, 73.87; H, 8.62; N, 3.75%. DESCRTPTTON 11 : f2S.3S -3-((3.5-Dichlorophenvl methvloxvV 2-phenvlpjperidine This compound was prepared from the compound of Description 3c and 3,5-dichlorobenzyl chloride, following the procedure described in Descriptions lc-e. Η NMR (CDC1 3 ) δ 1.49-1.53 (IH, m, CHH), 1.60-1.70 (IH, m, CHH), 1.82-1.95 (IH, m, CHH), 2.14-2.18 (IH, m, CHH), 2.79-2.87 (IH, m, NCHH), 3.27-3.31 (IH, m, NCHH), 3.60 (IH, s, CHO), 3.82 (IH, s, CHPh), 4.02-4.05 (IH, d, J=13Hz, OCHH), 4.31-4.35 (IH, d, J=13Hz, OCHH), 6.80 (2H, s, ArH), 7.15 (IH, s, ArH), 7.25-7.35 (5H, m, ArH). Found: C, 58.24; H, 5.38; N, 3.91. Calcd. for C 18 H 19 C1 2 N0.HC1: C, 58.01; H, 5.41; N, 3.76%. DESCRIPTION 1 : (2S.3S 3-((3-Chloro-5-methv1phenvn methvloxv)-2-phenvlpiperidine This compound was prepared from the compound of Description 3c and 3-chloro-5-methylbenzyl bromide, following the procedure described in Descriptions lc-e: mp 235-237°C. MS (CI+) m/z 316 (M++H, 100%). Found: C, 64.68; H, 6.50; N, 3.98. Calcd. for C19H22CINO.HCI: C, 64.78; H, 6.58; N, 3.98%. DESCRIPTION 13: (2S.3S)-3-((3.5-Bis(trifluoromethvDphβnyl) methyloxy)-2-(diphenylmethyl pyrrolidinium hydrochloride (a) N-*-Butvloxvcarbonvl-(SVdiphenvlalanal A solution of methyl sulfoxide (4.4ml) in dichloromethane (13ml) was added dropwise to a cooled (-78°C) solution of oxalyl chloride (4ml) in dichloromethane (50ml). After 15 min, a solution of N-*-butyloxycarbonyl-(S)-diphenylalanol (lOg) in dichloromethane (150ml) was added dropwise at -30°C. The solution was allowed to stir for 30 min, triethylamine (17ml) was added and the solution was allowed to warm to -10°C. Ice- water (200ml) was added to the solution which was then poured onto hexane (600ml). The organic phase was separated, washed successively with citric acid (200ml), saturated aqueous sodium bicarbonate (2 x 150ml), brine (1 x 150ml) then dried (MgS0 4 ) and concentrated in vacuo to leave a white crystalline sohd. X H NMR (250MHz, CDC1 3 ) δ 1.42 (9H, s, C(CH 3 ) 3 ), 4.48 (IH, d), 4.86 (IH, d), 5.10 (IH, t), 7.26 (10H, m, ArH), 9.6 (IH, s, CHO). fb) N- -Butyloxycarbonyl-l-fdiphenylmethyll-Σ-hvdroxy- pent-4-envl-l-amine A solution of N-£-butyloxycarbonyl-(S)-diphenylalanal (10.9g) in tetrahydrofuran (60ml) was added dropwise to a soluton of allyl magnesium chloride (2M in tetrahydrofuran, 36ml) at -10°C. After 30 min the mixture was poured onto ice- cold saturated aqueous ammonium chloride and the resulting mixture was extracted with ethyl acetate (3 x 150ml). The combined organic extracts were washed with brine (1 x 100ml), then dried (MgS0 4 ) and concentrated in vacuo. The residue was purified by chromatography on silica gel using hexane in ethyl acetate (gradient elution of 9:1 to 4:1) as eluant to afford the compound as a white sohd. *H NMR (360MHz, CDC1 3 ) δ 1.42 (9H, s, (CH 3 ) 3 ), 2.22 (2H, m), 2.68 (3H, brs), 3.48 (t), 3.57 (IH, m), 3.86 (IH, s), 4.07 (d, J = 11Hz), 5.04 (IH, m), 5.71 (IH, m), 6.97-7.36 (10H, m, ArH). (c) Σ-^S.δ-BisftrifluoromethvDphenvDmethyloxyVN-t- butvloxvcarbonvl-l-(diphenvlmethvlVpent-4-envl-l-amine Sodium hydride (80% in oil, 0.53g) was added to a solution of 3,5-bis(trifluoromethyl)benzyl bromide (5ml) and the compound of (13b) above (5g) in dimethylformamide (8ml). After stirring for lh water (80ml) was added and the mixture was extracted with ethyl acetate (3 x 100ml). The combined organics extracts were washed with brine (1 x 100ml) then dried (MgS0 4 ) and concentrated to leave an oil which was purified on silica using hexane in ethyl acetate as eluant (gradient elution of 97:3 to 4:1). This afforded the title compound as a colourless oil. Η NMR (360MHz, CDC1 3 ) δ 1.25 (s), 1.30 (s), 2.35 (m), 3.31 (m), 3.40 (dd, J = 5.2, 8.3Hz), 3.97 (d), 4.27 (d), 4.38 (m), 4.65 (m), 4.85 (d), 5.16-5.02 (m), 5.77 (m), 7.35-7.13 (m), 7.76 (s), 7.85 (s). (d) (2S,3S)-3-((3,5-Pis(trifl prQm9thyl)phepγl) methvloxv-2-(diphenvlmethvl)pvrrolidinium hydrochloride A solution of the compound of (c) above (5.2g) in dichloromethane (40ml) and methanol (40ml) was treated with a stream of ozone in oxygen at -78°C for lh. Methyl sulfide (3ml) was added and the mixture was warmed to 23°C and concentrated in vacuo. The residue was dissolved in chloroform (50ml), triethylsilane (5.6ml) was added followed by dropwise addition of a solution of trifluoroacetic acid (6.9ml) in chloroform (5ml). After lh the solvent was evaporated in vacuo and trifluoroacetic acid (10ml) was added to the residue. After stirring for 30 min the mixture was concentrated in vacuo and the residue was partitioned between dichloromethane and saturated aqueous sodium bicarbonate. The organic layer was dried and concentrated to leave a brown oil. This was purified on silica gel eluting with dichloromethane/methanol (99:1) to provide the title compound as the free base. This was converted to the salt by treatment with methanolic hydrogen chloride: mp >230°C. [α] 23 D = +46.6° (c=l, CH 3 OH). Found: C, 59.95; H, 4.74; N, 2.63%. Calcd. for C, 60.11; H, 4.73; N, 2.70%. DESCRTPTTON 14: (2R-3S 3-((3.S-Bisrtrifluoromethvl,phenvl methvloxv)-2-fdiphenvlmethvl)pvrrolidinium hydrochloride The title compound was prepared from N-t- butyloxycarbonyl-(R)-diphenyIalanol by a procedure analagous to that described in Description 13: mp > 230°C. [αP D = +12.1° (c=l, CH 3 OH). DESCRIPTION 15: (2S.3S)-3-(r3.5-Dichlorophenyl methyloxy)- 2-(diphenvl methvDpvrrolidinium hydrochloride (a) N-f-Butyloxycarbonyl-2-((3.5-dichlorophenyl) methyloxy-l-(diphenylmethyl)pent-4-enyl-l-amine The compound of Description 13b was alkylated with 3,5- dichlorobenzyl chloride by a procedure analagous to that described in Description 13c, to afford the title compound as an oil. NMR (360MHz, CDC1 3 ) δ 1.25 (9H, s), 2.41-2.27 (2H, m), 3.32 (IH, m), 4.07 (IH, d, J=llHz), 4.13 (IH, d, J=12Hz), 4.30 (IH, d, J=12Hz), 4.65 (2H, m), 5.13 (2H, ), 5.76 (IH, ), 7.35- 6.60 (13H, ). MS (CI+) m/z 526, 528 (M++1, 100%, 80%). (b) (2S.3S)-3-((3.5-Dichlorophenyl)methyloxy -2- (diphenylmethvDpyrrolidinium hydrochloride The compound of Description 15a above was treated with ozone followed by triethylsilane-trifluoroacetic acid by a procedure analagous to that described in Description 13d to afford the title compound as a white crystalline solid: mp>230° C. Found: C, 64.52; H, 5.34; N, 3.12. Calcd. for C, 64.23; H, 5.39; N, 3.12%. DESCRIPTION 1& f2S.3S 3-f ( 3-f--Bntv1-5-ch1oro π hgτ methyloxy)-2-phenylpiperidinium hydrochloride (a) 4-f-Butvl-2-cMoro-6-(methylthiomβthvDamlinβ 4-i-Butyl-2-chloroaniline (30g) was dissolved in dichloromethane (1.21) and the solution was cooled to -5°C. N- cMorosucdnimide (21.7g) was added portionwise to the vigorously stirred solution and stirring was continued for lh. Dimethyl sulfide (35ml) was added to the solution (-5°C) and stirring was continued for a further lh. The solution was then cooled to -65°C and triethylamine (27ml) was added. This solution was allowed to warm to room temperature overnight. The solution was evaporated to half volume, washed with sodium hydroxide (IN), water and brine successively. The organic solution was dried and evaporated and the residue was purified on silica using hexane to 3% ether in hexane as eluant. This afforded the product (31.2g) as a red oil. Η NMR (CDC1 3 , 250MHz) δ 1.27 (9H, s, (CH 3 ) 3 ), 1.99 (3H, s, SCH- 3 ), 3.69 (2H, s, CE 2 SCH 3 ), 4.38 (2H, br s, NH 2 ), 6.92 (IH, d, J=2.0Hz, ArH), 7.21 (IH, d, J=2.0Hz, ArH). MS (CI+) m/z 244 (M++1, 100%). (b) 4-t-Butvl-2-chloro-6-methvlamline 4-^-Butyl-2-chloro-6-(methylthiomethyl)aniline (1.3g) was dissolved in methanol (50ml) and Raney nickel (prewashed to pH 7) was added portionwise until t.l.c. indicated all starting material had reacted (ether-hexane, 1:10). The Raney nickel was removed by filtration through celite and the filtrate was evaporated. The residue was dissolved in ether and washed with brine, dried (MgS0 4 ) and evaporated. The residue was purified on silica using hexane - 5% ether in hexane as eluant to afford the product as a yellow liquid. -Η. NMR (360MHz, CDC1 3 ) δ 1.26 (9H, s, (CH 3 ) 3 ), 2.19 (3H, s, CH 3 ), 3.97 (2H, s, NH 2 ), 6.97 (IH, d, J=2.0Hz, ArH), 7.14 (IH, d, J=2.0Hz, ArH). (c) 3-fr-Butyl-5-chlorotoluene 4-£-Butyl-2-chloro-6-methylaniline (1.97g) was dissolved in ethanol (50ml); sulphuric add (1.88ml, cone.) was added dropwise and the resulting blue solution was heated at reflux. Sodium nitrite (1.72g) was added portionwise over 30 min. The resulting mixture was heated at reflux for a further 30 min, then cooled and was poured onto ice-water and extracted with ether (2 x 50ml). The ethereal extract was dried (MgS0 4 ) and evaporated and the residue was purified on silica gel using hexane as eluant. This afforded the product as a colourless oil. Ή NMR (360MHz, CDC1 3 ) δ 1.29 (9H, s, (CH 3 ) 3 ), 2.31 (3H, s, CH 3 ), 6.98 (IH, brs, ArH), 7.05 (IH, brs, ArH), 7.15 (IH, brs, ArH). MS (CI-) m z 181 (M+-H, 100%). (d) 3-£-Butyl-5-chlorobenzyl bromide 3-t-Butyl-5-chlorotoIuene (5.7g) was dissolved in carbon tetrachloride (80ml) and N-bromosucdnimide (5.56g) was added followed by benzoyl peroxide (750mg). This mixture was heated at reflux for 6h. The mixture was cooled, filtered through celite and the filtrate was concentrated in vacuo. The residue was purified by chromatography on silica using hexane as eluant. This afforded the title compound as a colourless liquid. Η NMR (360MHz, CDC1 3 ) δ 1.31 (9H, s, (CH 3 ) 3 ), 4.42 (2H, s, CH 2 ), 7.20 (IH, t, J=1.5Hz, ArH), 7.26 (IH, t, J=1.5Hz, ArH), 7.28 (IH, t, J=1.5Hz, ArH). (e) (2S.3S -l-i-Butyloxycarbonyl-3-rr3-^-butyl-5-chloro- phenv methyloxy)-2-phenylpiperidine. (+)-cis-3-Hydroxy-2-phenylpiperidine (Description 3c) was reacted with 3-£-butyl-5-chlorobenzyl bromide (Description 15d above) according to the procedure detailed in Description lc-d to afford the title compound. Η NMR (360MHz, CDC1 3 ) δ 1.27 (9H, s, C(CH 3 ) 3 ), 1.46 (9H, s, C(CH 3 ) 3 ), 1.52-1.66 (2H, m), 1.8-2.0 (2H, m), 2.69 (IH, td, J=3.5Hz, 13.0Hz, NCHH), 3.81 (IH, q, J=5Hz, NCHH), 3.92 (IH, brd, CHO), 4.60 (2H, q, J=12Hz, OCH 2 ), 5.70 (IH, brs, CHPh), 7.10 (IH, s, ArH), 7.18 (IH, s, ArH), 7.22 (2H, s, ArH), 7.43-7.47 (2H, m, ArH), 7.57-7.59 (2H, m, ArH). if} The compound of Description 15e above was dissolved in methanolic hydrogen chloride overnight. The solution was then concentrated in vacuo and the residue triturated with ether. This afforded the title compound as a white crystalline powder: mp 210-211°C. Η NMR (360MHz, DMSO-d 6 ) δ 1.21 (9H, s, C(CH 3 ) 3 ), 1.66-1.80 (2H, m, CH 2 ), 1.86-1.93 (IH, m, CHH), 2.18-2.22 (IH, m, CHH), 3.04-3.11 (IH, m, NCHH), 3.3 (IH, m, NCHH), 3.88 (IH, brs, CHO), 4.14 (IH, d, J=12Hz, OCHH), 4.52 (IH, s, CHPh), 4.53 (IH, d, J=12Hz, OCHH), 6.95 (IH, s, ArH), 7.00 (IH, s, ArH), 7.24 (IH, t, J=1.8Hz, ArH), 7.3- 7.5 (5H, m, ArH), MS (CI + ) m/z 358 (M + +1, 100%). Found: C, 66.68; H, 7.29; N, 3.40. Calcd. for C, 67.00; H, 7.41; N, 3.55%. DESCRIPTION Hi ( 2R*.3R* 3-ff3-Carhom e thoxvphenvl ) methvloxv -2-phenvlpiperidine (a) (2R*.3R*)-l-£-Butyloxycarbonyl-3-((3-cvanophenyl; methyloxy)-2-phenylpiperidine This compound was prepared from 1-έ-butyloxycarbonyl- 3-hydroxy-2-phenylpiperidine (Description lc) and α-bromo-m- tolunitrile according to the procedure described in Example Id. Η NMR (360MHz, CDC1 3 ) δ 1.49 (9H,s, (CH 3 ) 3 ), 1.6-1.72 (2H, m), 1.87-1.99 (2H, m), 2.72 (IH, dt, J = 13, 4Hz, NCHH), 3.80- 3.95 (2H, m, CHO + NCHH), 4.65 (2H, q, J = 12Hz, OCH 2 ), 5.69 (IH, brs, CHPh), 7.1-7.5 (9H, m, ArH). (b) (2R*.3R*)-3-((3-Carbomethoxyphenyl)methyloxy-2- phenylpiperidine The compound of (a) above (1.5g) was dissolved in methanol (15ml) and concentrated hydrochloric add (aqueous, 10ml) was added. The contents were heated at reflux for 12h. The solution was cooled and evaporated to leave a brown oil. This was dissolved in methanoHc hydrogen chloride and the resulting solution was stirred overnight, then evaporated. The residue was purified by dispersion between water and ethyl acetate and the organic layer was dried (MgS0 4 ) and concentrated. The residue was purified by chromatography on siHca using a gradient elution of 2%-6% methanol in dichloromethane. The first compound to elute was characterised as the hydrochloride salt by dissolution in methanoHc hydrogen chloride. The salt was recrystalHsed from ethyl acetate methanol: mp 206-208°C. (c) (2R*.3R*V3-((3-(Carbomethoxy)phenyl>methyloxy)- 2-phenvlpiperidine i H NMR (CDC1 3 ) δ 1.45-1.71 (2H, m, NCH 2 CH 2 CH 2 ), 1-83- 2.02 (IH, m, NCH 2 CHH), 2.12-2.23 (IH, m, NCH 2 CHH), 2.44 (IH, bs, NH), 2.77-2.90 (IH, m, NCHH), 3.24-3.34 (IH, m, NCHH), 3.61-3.66 (IH, bs, CHO), 3.8-3.83 (IH, d, J = 15Hz, CHPh), 3.90 (3H, s, COOCH 3 ), 4.15 (IH, d, J=12Hz, OCHH), 4.39 (IH, d, J=12Hz, OCHH), 7.09 (7H, m, ArH), 7.71 (IH, bs, ArH), 7.83-7.89 (IH, m, ArH); MS (CI+) m/z 326 (M++1, 100%). Found: C, 66.31; H, 6.36; N, 3.80. Calcd. for C 20 H 23 NO 3 .HCl: C, 66.38; H, 6.69; N, 3.87%. DESCRTPTTON 18: (2R*.3R*)-3-((3-Carboxamidophenv1 methyloxy.-2-phenylpiperidine The second compound to elute from the column described in 17b above was isolated as a colourless oil. r H NMR (360MHz, CDC1 3 ) δ 1.2-2.2 (4H, m), 2.82 (IH, mc), 3.27 (IH, mc), 3.66 (IH, s), 3.82 (IH, s), 4.16 (IH, d, J = 12Hz, OCHH), 4.48 (IH, d, J = 12Hz, OCHH), 5.53 (IH, brs, CONHH), 6.18 (IH, brs, CONHH), 7.0-7.4 (9H, m, ArH). DESCRIPTION 19: (2R*.3R*)-3-((2-Methoxy-3-nitrophenyl) methyloxy -2-phenylpiperidinium hydrochloride This compound was prepared from the compound of Description lc and 2-methoxy-5-nitrobenzyl bromide, following the procedure described in Descriptions lc-e. mp 246-248°C. MS (CI+) m/z 343 (M++1, 45%). Found: C, 60.52; H, 5.96; N, 7.45. Calcd. for C^H^NA-HCl: C, 60.24; H, 6.12; N, 7.39%. DESCRIPTION 20: (2R*.3R*)-3-.(5-Amino-2-methoχyphenyl) methyloxy)-2-phenylpiperidinium hydrochloride The compound of Description 19 (0.342g) was dissolved in methanol (20ml) with hydrochloric add (1ml, 2N). Palladium on charcoal (50mg) was added and the mixture placed under an atmosphere of hydrogen for lh at room temperature. The solvent was removed in vacuo and the residue basified with sodium hydroxide (2M). This solution was extracted with ethyl acetate and the organic extracts were dried (MgS0 4 ) and concentrated to leave a brown oil; this was purified by column chromatography on siHca using 8% methanol in dichloromethane as eluent. The resulting oil was characterised as the salt prepared by treatment with methanolic hydrogen chloride: mp 241-243°C. The foUowing piperidines were prepared according to the procedures outlined in Descriptions 1 and 3, using the appropriate benzyl hahde. DESCRIPTION 21: (2S.3S)-2-Phenyl-3-f(3-(trifluoromethyl) phenyl)methyloxy)piperidine iH NMR (CDC1 3 ) δ 1.4-2.2 (4H, m), 2.45 (IH, brs), 2.83 (IH, td, J=13Hz and 4Hz), 3.3 (IH, m), 3.64 (IH, d, J=2Hz), 3.82 (IH, d, J=2Hz), 4.13 (IH, d, J=12Hz, OCHH), 4.42 (2H, J=12Hz, OCHH), 7.75 (m, 9H, ArH). DESCRTPTTON 22: (2S-3SV3-fr3.4-Dich1ornphenvl,methyloxy 2- p henylpiperi irivrn h y drochloride iH NMR (DMSO-d 6 ), 1.65-1.8 (2H, m), 1.8 (IH, m), 2.16 (IH, d, J=12Hz), 3.05 (IH, m), 3.25 (IH, m), 3.83 (IH, s), 4.12 (IH, d, J=12Hz), 4.5 (2H, m), 7.05 (IH, dd, J=7 & 2Hz), 7.28 (IH, d, J=2Hz), 7.35-7.5 (6H, m), 9.05 (IH, br s), 9.8 (IH, br s). DESCRIPTION 23: (2S.3S)-3-f(2.3-Dimethylphenyl)methyloxyV 2-phenylpiperi * ym hydrochloride Ethyl acetate (10ml) was saturated with hydrogen chloride by passing HCl gas for 5 min and a solution of 0.254g of (2S,3S)-l-^-butoxycarbonyl-3-((2,3-dimethylphenyl)methoxy)-2- phenylpiperidine (prepared according to Description 3d) in 7ml of ethyl acetate was added. After stirring for 2h, the reaction mixture was concentrated in vacuo. The residual white sohd was washed with ether, filtered and dried to obtain 0.23g of (2S,3S)-3-((2,3-dimethylphenyl)methyloxy)-2- phenylpiperidinium hydrochloride. *H NMR (DMSO-d β ) δ 1.6- 1.9 (3H, m), 1.75 (3H, s), 2.15 (3H, s), 2.2 (IH, m), 3.05 (IH, m), 3.25 (IH, m), 3.84 (IH, s), 4.05 (IH, d, J=14Hz), 4.45 (IH, d, J=14Hz), 4.48 (IH, s), 6.95-7.5 (8H, m), 8.8 (IH, br s), 9.4 (IH, br s). DESCRIPTION 24: (2S.3S)-3-((3- -Butylphenyl)methyloxyV2- phenylpiperidinium hydrochloride Η NMR (360MHz, CDC1 3 ) δ 1.21 (9H, s, C(CH 3 ) 3 ), 1.45 (3H, s), 1.52-1.67 (2H, m, CH 2 ), 2.04-2.12 (IH, m, CHH), 2.30- 2.34 (IH, m, CHH), 2.93-2.96 (IH, m, NCHH), 3.54 (IH, d, J=13Hz, NCHH), 3.72 (IH, s, NCHCHO), 4.14 (IH, d, J=2Hz, NCHCHO), 4.28-4.36 (2H, q, J=13Hz, OCHH), 6.87-6.89 (IH, m, ArH), 7.05 (IH, s, ArH), 7.11-7.15 (IH, m, ArH), 7.20-7.34 (4H, m, ArH), 7.55-7.58 (2H, m, ArH). MS (CI+) m/z 323 (M++1, 100%). DESCRIPTION 25: (2R*,3R*)-3-((3,5-Dimethγlph W yl) methyloxy)-2-phenylpiperidinium hydrochloride NMR (360MHz, CDC1 3 ) δ 1.48 (m), 1.62 (m), 1.86 (m), 2.20 (s), 2.82 " (ddd, J=3.0. 3.0, 12.6Hz), 3.26 (dt, J=2.15, 2.15, 12.5Hz), 3.63 (s), 3.78 (s), 4.10 (d, J=12.0Hz), 4.33 (d, J=12.0Hz), 6.31 (s), 7.2-7.4 (m). MS (CI + ) m/z 296 (M + +1). DESCRIPTION 2ft (2R*.3R* 3-((3.fi- Bis(trifluoromethyl)phenyl) methyloxy)-2-(3- chlorophenvDpiperidine (a) Methyl-4-nitrobutyrate and 3-chlorobenzaldehyde were reacted in an analogous manner to that described in Description la to give 2-(3-chlorophenyl)-3-nitro-6-oxopiperidine: mp 131- 133°C. Η NMR (360MHz, CDC1 3 ) δ 2.26-2.36 (IH, m), 2.50-2.72 (3H, m), 4.66-4.71 (IH, m), 5.24-5.28 (IH, d), 6.57 (IH, s), 7.17- 7.40 (4H, m). (b) The product of part a) was treated analogously to that described in Description lb to give 2-(3-chlorophenyl)-3.6-dioxo piperidine: mp 144-147°C. Η NMR (360MHz, CDC1 3 ) δ 2.8 (4H, m), 5.0 (IH, d), 6.4 (IH, s), 7.22-7.42 (4H, m). c) The product of part b) was treated analogously to that described in Description lc and 3a to give cts-2-f3-chlorophenvD- 3-hvdroxypiperidine tosylate salt: mp > 250°C. -Η. NMR (360MHz, CDC1 3 ) δ 1.60-2.07 (4H, m), 2.28 (3H, s), 3.00-3.11 (IH, m), 4.02 (IH, s), 4.62-4.66 (IH, d), 5.96 (IH, s), 7.10-7.20 (2H, d), 7.41-7.59 (6H, m). d) The product of part c) was treated analogously to that described in Description lc to give cis- l-t-butyloxycarbonyl-2-(3- cMorophenyl)-3-hydroxypiperidine as a dear, viscous oil. -Η. NMR (360MHz, CDC1 3 ) δ 1.40 (9H, s), 1.61-1.90 (4H, m), 2.88- 3.01 (IH, ddd), 3.93-3.99 (IH, dd), 4.03-4.10 (IH, m), 5.33 (IH, d), 7.20-7.26 (2H, m), 7.34-7.38 (IH, m), 7.47-7.52 (IH, m). m z (CI-) 310, 312; m/z (CI + ) 312, 314. e) The product of part d) and 3,5- bis(trifluoromethyl)benzylbromide were treated in an analogous manner to that described in Description Id to give cis-3-((3.5- bis(trifluoromethvDphenv methvloxv)-l-t-butvloxv-carbonvl-2- r3-chlorophenyr.piperidine. H NMR (250MHz, CDC1 3 ) δ 1.24- 1.30 (IH, m), 1.47 (9H, s), 1.60-2.00 (3H, m), 2.67-2.80 (IH, ddd), 3.81-4.01 (2H, m), 4.8 (2H, s), 5.61-5.67 (IH, d), 7.23-7.27 (2H, m), 7.39-7.44 (IH, m), 7.6 (IH, s), 7.78 (2H, s), 7.8 (IH, s). f) The product of part e) was treated in an analogous manner to that described in Description le to give c£s-3-(f3.5- bisftrifluoromethyl)phenyl)methyloxy)-2-f3-cMorophenvD piperidine hydrochloride salt, mp = 158°C. Η NMR (360MHz, DMSO-d e ) δ 1.70-1.96 (4H, m), 2.19-2.28 (IH, m), 3.02-3.13 (IH, m), 3.84 (IH, s), 4.35-4.39 (2H, d), 4.60 (IH, s), 4.79-4.85 (2H, d), 7.39-7.44 (3H, m), 7.58 (IH, s), 7.84 (2H, s), 7.97 (IH, s), 9.2 (br s), 10.05 (br s). Found: C, 50.44; H, 4.13; N, 3.01. C 20 H 18 C1F 6 NO.HC1 requires C, 50.65; H, 4.04; N, 2.95%. m z (CI + ), 438, 440. DESCRIPTION 27: 2S.3S.-3-((3-Fluoro-5-methylphenyl) methvloxv)-2-phenvlpiperidine mp 219-221°C. Η NMR (360MHz, CDC1 3 ) δ 1.50-1.68 (2H, m), 2.11-2.15 (IH, m), 2.20 (3H, s, CH 3 ), 2.31-2.35 (IH, m), 2.94- 2.98 (IH, m, NCHH), 3.55-3.58 (IH, d, J = 12Hz, NCHH), 3.69 (IH, bs, CHO), 4.15-4.18 (IH, m, CHPh), 4.18 (IH, d, J = 13Hz, OCHH), 4.33 (IH, d, J = 13Hz, OCHH), 6.47 (IH, d, ArH), 6.59 (IH, s, ArH), 6.66 (IH, d, ArH), 7.26-7.37 (3H, m, ArH), 7.52- 7.54 (2H, m, ArH). MS (CI+) m/z 300 (M++1, 100%). DESCRIPTION 28: (3R* 3-. te.δ-Bisftrifluoromethyl fohenyl ) methyloxy)-2-methyl-2-(2R*)-2-phenvIpiperidine (a) 3,6-Dioxo-2-phenylpiperidine (Description lb) (5g) was dissolved in dimethylformamide (25ml) at 0°C. Sodium hydride (873mg, 80% dispersion in oil) was added portionwise and the mixture stirred for 15 min. Methyl iodide was added (1.8ml) and the mixture was stirred for 12h. The mixture was diluted with water (250ml) and extracted with ethyl acetate (3 x). The combined organic extracts were washed with brine, dried (MgS0 4 ) and concentrated to leave a solid: 3,6-dioxo-2-methyl-2- phenylpiperidine. (b) The ketone of (a) above (3.2g) was suspended in methanol under nitrogen and the temperature brought to -40°C. Sodium borohydride (0.3g) was added portionwise. The mixture was stirred for 30 min and then concentrated in vacuo, azeotroping with tetrahydrofuran. Borane tetrahydrofuran complex (64ml, l.OM in tetrahydrofuran) was added and the mixture was heated at reflux overnight. The mixture was cooled and quenched carefully with methanol, and the mixture was then concentrated in vacuo. The resulting residue was dissolved in ethanol (100ml) and potassium carbonate (4.2g) was added. The mixture was heated at reflux for 12h. The mixture was cooled and evaporated and the residue was extracted with ethyl acetate and water. The organic extract was washed with brine, dried (MgS0 4 ) and evaporated to afford 3-hvdroxy-2-methyl-2- phenylpiperidine as a white solid. Η NMR (360MHz, CDC1 3 ) δ 7.79 (2H, d, ArH), 7.40 (2H, t, ArH), 7.15-7.19 (IH, m, ArH), 3.89 (IH, mc), 2.89-3.01 (2H, m), 1.67-1.91 (4H, m), 1.39 (3H, s, CH 3 ). (c) The alcohol of (b) above (3g) was dissolved in dichloromethane (50ml) and di-i-butyldicarbonate (3.48g) was added. The solution was aHowed to stir for 12h. The solution was concentrated in vacuo and the residue was purified by chromatography on siHca using ethyl acetate in petrol (20:80) as eluent. This afforded N-t-butyloxycarbonyl-2-hydroxy-2-methyl- 2-phenylpiperidine as a dear oil. r H NMR (250MHz, CDC1 3 ) δ 1.08 (9H,s, (CH 3 ) 3 ), 1.80 (3H, s, CH 3 ), 1.6-2.0 (4H, m), 3.6-3.74 (2H, m), 3.8-3.92 (IH, m, CHO), 7.2-7.36 (5H, m, ArH). (d) The alcohol of (c) above (2.2g) was dissolved in dry dimethylformamide (12ml). Sodium hydride was added (0.36g, 60% dispersion in oil) portionwise and the mixture was allowed to stir at room temperature for 30 min. 3,5- Bis(trifluoromethyl)benzyl bromide (3.5g) was added dropwise and the mixture was aUowed to stir for 5h. The mixture was diluted with aqueous ammonium chloride, extracted with ethyl acetate and the organic extract was washed with brine, dried (MgS0 4 ) and evaporated in vacuo. The residue as purified by column chromatography on siHca using a gradient elution, 100% petrol to 10% ethyl acetate in petrol as eluant, to afford the product 3-((3,5-bis(trifluoromethyl)phenyl)methyloxy-l-£- butyloxycarbonyl-2-methyl-2-phenylpiperidine as a colourless oil. i H NMR (360MHz, CDC1 3 ) δ 1.13 (9H, s (CH 3 ) 3 ), 1.85 (3H, s, CH 3 ), 1.85-1.99 (4H, m, CH 2 CH 2 ), 3.48 (IH, brs, NCHH), 3.68- 3.75 (IH, m, NCHH), 3.80-3.85 (IH, m, CHO), 3.85 (IH, d, J = 12Hz, OCHH), 4.36 (IH, d, J = 12Hz, OCHH), 7.17-7.32 (5H, m, ArH), 7.42 (2H, s, ArH), 7.71 (IH, s, ArH). (e) The compound of (d) above (2.1g) was dissolved in trifluoroacetic add (30ml) for 10 min and was then evaporated in vacuo. The residue was dissolved in dichloromethane, washed with sodium hydroxide (2M), water and brine, then dried (MgS0 4 ) and concentrated in vacuo. MethanoHc hydrogen chloride was added to the residue and when dissolved the solvent was evaporated. The residue was triturated with ether to afford the product as a white powder: (3R*)-3-((3,5- Bis(trifluoromethyl) phenyl)methyloxy)-2-methyl-(2R*)-2- phenyl-piperidine. *H NMR (360MHz, DMSO) δ 1.67 (3H, s, CH 3 ), 1.70 (IH, m), 1.84-1.91 (IH, m), 1.99-2.06 (2H, m), 3.16 (IH, m), 3.33 (IH, m), 4.19 (IH, s), 4.29 (IH, d, J=12Hz, OCHH), 4.75 (IH, d, J=12Hz, OCHH), 7.29-7.33 (IH, m, ArH), 7.37-7.41 (3H, m, ArH), 7.54 (2H, s, ArH), 7.56 (IH, brs, ArH), 7.89 (IH, s, ArH). Found: C, 55.38; H, 4.92; N, 3.08 Calcd. for C 21 H 21 F 6 NO: C, 55.58; H, 4.89; N, 3.09%. DESCRIPTION 29: (2S.3S)-3-f(3.4-Dimethylphenyl) methyloxy)- 2-phenylpiperidine Η NMR (CDC1 3 ) δ 1.4-1.9 (3H, m), 2.11 (3H, s), 2.17 (3H, s), 2.1-2.3 (IH, m), 2.78 (IH, m), 3.25 (IH, m), 3.60 (IH, s), 3.76 (IH, s), 4.08 (IH, d, J=12Hz), 4.27 (IH, d, J=12Hz), 6.7 (2H, m), 6.92 (IH, d, J=9Hz), 7.2-7.5 (5H, m). DESCRIPTTON 30: (2S.3S.-3-f(3-rtsoPropoxv,phenvl) methvloxv.-2-phenvlpiperidine i H NMR (250MHz, CDC1 3 ) δ 1.6-1.9 (3H, m), 1.97 (IH, d, J=7Hz), 2.16 (IH, m), 3.05 (IH, m), 3.3 (IH, m), 3.84 (IH, s), 4.09 (IH, d, J=12Hz), 4.41 (IH, d, J=12Hz), 4.44 (IH, m), 4.5 (IH, s), 6.6 (2H, m), 6.72 (IH, m), 7.09 (IH, t, J=8Hz), 7.3-7.5 (5H, m). DESCRIPTION 31: (2S.3S)-3-f(3.5-Bis(trifiuoromethyl) phenyl)methyloxy)-2-(3-fluorophenyl)piperidine NMR (360MHz, CDC1 3 ) δ 1.66-1.9 (3H, m), 2.2-2.3 (IH, ), 2.43-2.5 (IH, m), 3.0-3.2 (IH, m), 3.98 (IH, s), 4.37 (IH, d, J=12Hz), 4.62 (IH, s), 4.79 (IH, d, J=12Hz), 7.04-7.46 (4H, m, ArH), 7.80 (2H, s, ArH), 7.96 (IH, s, ArH). EXA PLE ! 3-Amino-5-rff2R*.3R* -3-((3.5-Bis(trifluoromethvl)ph e nv1 methyloxy)-2-phenylpiperidino}methvn-1.2.4-oxadiazole Hydroxyguanidine sulphate hydrate (2.3g) was dissolved in water and freeze-dried overnight. Ethanol (35ml) and powdered molecular sieves (lg) were added to the sohd hydroxyguanidine and the suspension was stirred under nitrogen for 1 hour. Sodium (670mg) was added to the mixture whidi was stirred until aH sodium had reacted. The suspension assumed an orange colour at this time and was placed in an ultrasound bath for 15 min. The ester of Description 2 (1.4g) was added to the mixture which was then heated at reflux for 2h. The reaction mixture was cooled and filtered through ceHte. Ethanol was removed in vacuo and the residue was extracted into ethyl acetate and washed with water and brine. The organic layer was dried (MgS0 4 ) and evaporated. The residue was purified on siHca using 25% ethyl acetate in petrol as eluant. This afforded the product (800mg) as a solid which was recrystaHised from ether/hexane to afford colourless prisms: mp 160-161°C. iH NMR (360MHz, DMSO-d 6 ) d 1.47-1.54 (2H, m, CH 2 ), 1.85-1.9 (IH, m, CHH), 2.14-2.17 (IH, m, CHH), 2.35-2.40 (IH, m, CHHN), 2.99-3.02 (IH, m, CHH ), 3.35 (IH, d, J = 15.0Hz, N-CHH-oxadiazole), 3.60 (2H, brs, NCHCHO), 3.65 (IH, d, J = 15.0Hz, N-CHH-oxadiazole), 4.06 (IH, d, J = 13.0Hz, OCHH), 4.62 (IH, d, J = 13.0Hz, OCHH), 6.2 (2H, brs, NHg), 7.23-7.31 (3H, m, ArH), 7.42-7.44 (2H, m, ArH), 7.69 (2H, s, ArH), 7.93 (IH, s, ArH); MS (CI + ) m/z 501 ((M+l) + , 75%). Found: C, 54.81; H, 4.47; N, 11.2. Calcd. for C^H^ : C, 55.20; H, 4.43; N, 11.2%. EXAMPLE 2 5-rf(2R*.3R* 3-((3.5-Bis(trifluoromethyl>phenyl methvloxv)-2-phenvlpiperidino}methvll-3-methvl-1.2.4- oxadiazole Acetamideoxime (117mg) and powdered molecular sieves were suspended in dry tetrahydrofuran (10ml) and stirred under nitrogen for 1 hour. Sodium hydride (63mg of 60% suspension in oil) was added and the mixture heated to 50°C until all hydrogen evolution had ceased. The ester of Description 2 (500mg) was dissolved in tetrahydrofuran (2ml) and added to the above mixture. This mixture was heated at reflux for 2h, cooled, filtered through celite and evaporated in vacuo. The residue was dissolved in ethyl acetate and washed with water and then brine. The organic layer was dried (MgS0 4 ) and evaporated in vacuo. The residue was purified by medium pressure chromatography (Lobar) using 25% ethyl acetate in petrol as eluant. This afforded the product as a crystaUine soKd: mp 85-86°C; Η NMR (360MHz, DMSO-dg) d 1.47-1.54 (2H, m, CH 2 ), 1.85-1.89 (IH, m, CHH), 2.13-2.17 (IH, m, CHH), 2.31 (3H, s, CH 3 ), 2.34-2.40 (IH, m, CHHN), 2.98-3.01 (Hi, m, CHHN), 3.51 (IH, d, J = 15.0Hz, NCHH-oxadiazole), 3.60 (2H, s, NCHCHO), 3.81 (IH, d, J = 15.0Hz, NCHH-oxadiazole), 4.06 (IH, d, J = 13.0Hz, OCHH), 4.62 (IH, d, J = 13.0Hz, OCHH), 7.25-7.31 (3H, m, ArH), 7.43-7.45 (2H, m, ArH), 7.70 (2H, s, ArH), 7.93 (IH, s, ArH); MS (El) m z 500 ((M+l) + , 100%). Found: C, 57.94; H, 4.79; N, 8.23. Calcd. for C, 57.72; H, 4.64; N, 8.41%. EXAMPLE 3 (+) 3-Amino-5-r((2S.3SV3-((3.5-bi S ftrifluoromethv phenyl)methyloxy)-2-phenylpiperidino)methvn-1.2.4-oxadiazole The title compound was prepared from the ester of Description 4 using the procedure described in Example 1: mp 138-139°C; [aP D = +147.7° (c=l, MeOH). . Η NMR (360MHz, CDC1 3 ) d 1.47-1.50 (2H, m, CH 2 ), 1.85-1.89 (IH, m, CHH), 2.14-2.17 (IH, m, CHH), 2.35-2.41 (IH, m, CHHN), 2.99-3.02 (IH, m, CHHN), 3.29 (IH, s, NCHCHO)^ 3.33 (IH, d, J = 15.0Hz, NCHH-het), 3.65 (IH, d, J = 15.0Hz, NCHH-het), 3.60 (IH, brs, NCHPh), 4.05 (IH, d, J = 13.0Hz, OCHH), 4.62 (IH, d, J = 13.0Hz, OCHH), 6.20 (2H, s, NH 2 ), 7.23-7.31 (3H, m, ArH), 7.42-7.44 (2H, m, ArH), 7.69 (2H, s, ArH), 7.93 (IH, s, ArH); MS (CI + ) m/z 501 (M+l + , 75%). Found: C, 54.81; H, 4.47; N, 11.2. Calcd. for C^H^N : C, 54.98; H, 4.54; N, 11.30%. EXAMPLE 4 3-rf(2R*.3R*V3-f(3.B-BiB(triflιιoromethvl^hβnvn methyloxy)-2-phenylpiperidino}methyllpyridinium hydrochloride The compound of Description 1 (410mg), 3-picolyl chloride (167mg) and potassium carbonate were suspended in dimethylformamide (3ml) and the mixture heated at 60°C for 12h. The mixture was cooled, diluted with water (50ml) and extracted with ethyl acetate (2 x 10ml). The organic phase was washed with brine, dried (MgS0 4 ) and evaporated. The residue was purified on siHca using a gradient elution of 25-50% etiiyl acetate in petrol. The product was dissolved in ethereal hydrogen chloride to form the dihydrochloride salt which was recrystaHised from benzene: mp 198-200°C. *H NMR (360MHz, DMSO-d 6 , 353K) d 1.68-1.82 (2H, m, CH 2 ), 2.09-2.18 (2H, m, CH 2 ), 3.06 (IH, mc, CHHN), 3.37 (IH, mc, CHHN), 3.89 (IH, s, NCHCHO), 4.16 (IH, brd, NCHH-pyridine), 4.20 (IH, brd, NCHH-pyridine), 4.26 (IH, d, J = 13.0Hz, CHHO), 4.56 (IH, brs, NCHPh), 4.72 (IH, d, J = 13.0Hz, CHHO), 7.37-7.41 (3H, m, ArH), 7.60-7.64 (IH, m, ArH), 7.71-7.72 (2H, m, ArH), 7.86 (IH, s, ArH), 7.89 (2H, s, ArH), 8.08 (IH, d, J = 8.0Hz, ArH), 8.64 (IH, s, ArH), 8.68 (IH, d, J = 5.0Hz, ArH); MS (CI + ) m/z 495 (M++1, 60%); Found: C, 52.45; H, 4.90; N, 4.52. Calcd. for C 26 H 24 P 6 N 2 θ.2HC1.1.5H 2 0 : C, 52.54; H, 4.92; N, 4.71%. EXAMPLE 5 2-r(r2R*.3R*V3-(r3.5-Bis(trifluoromethvDphenyl methyloxyl-Σ-phenylpiperidinolmethvnpyridinium hydrochloride The compound of Description 1 was reacted with 2-picolyl chloride foUowing the procedure illustrated in Example 4: mp 175-180°C. NMR (360MHz, DMSO-d 6 )_d 1.65-1.83 (2H, m, CH 2 ), 2.08-2.15 (2H, m, CH 2 ), 3.16-3.20 (IH, m, CHHN), 3.30-3.40 (IH, m, CHHN), 3.70 (IH, s, NCHCHO), 4.18 (IH, d, J = 14.0Hz, CHH-pyridine), 4.23 (IH, d, J = 14.0Hz, CHH- pyridine), 4.30 (IH, d, J = 13.0Hz, OCHH), 4.79 (IH, d, J = 13.0Hz, OCHH), 4.78 (IH, s, CHPh), 7.24 (IH, d, J = 7.5Hz, ArH), 7.36-7.4 (3H, m, ArH), 7.47-7.51 (IH, m, ArH), 7.62 (2H, mc, ArH), 7.85 (IH, dt, J = 7.5, 2.0Hz, ArH), 7.94 (2H, s, ArH), 7.97 (IH, s, ArH), 8.65 (IH, d, J = 7.5Hz, ArH); MS (CI + ) m/z 495 (M+l) + , 100%). Found: C, 53.01; H, 4.79; N, 4.69. Calcd. for : C, 53.30; H, 4.82; N, 4.78%. EXAMPLE 6 2-r((2R*.3R* -3-((3.5-Bis(trifluoromethylιphenyl) methyloxyV2-phenylpiperidino)methvHbenzimidazole The compound of Description 1 was reacted with 2-(chloromethyl)benzimidazole foUowing the procedure ffiustrated-in Example 4: mp 152-153°C. Η NMR (360MHz, DMSO-d 6 ) d 1.44-1.59 (2H, m, NCH 2 CH 2 CH 2 ), 1.85-1.89 (IH, m, CHHCH 2 N), 2.15-2.18 (2H, m, NCHH+CHHCH 2 N), 2.86-2.89 (IH, m, NCHH), 3.15-3.19 (IH, d, J = 14.0Hz, NCHH-i idazole), 3.57 (IH, s, NCHCHO), 3.63 (IH, s, NCHCHO), 3.80-3.84 (IH, d, J = 14.0Hz, NCHH-imidazole), 4.10-4.13 (IH, d, J = 13.0Hz, -OCHH), 4.63-4.66 (IH, d, J = 13.0Hz, -OCHH), 7.07-7.15 (2H, m, ArH), 7.24-7.34 (3H, m, ArH), 7.43-7.52 (2H, m, ArH), 7.60-7.62 (2H, m, ArH), 7.67 (2H, s, ArH), 7.94 (IH, s, ArH), 12.10 (IH, s, NH); MS (CI + ) m/z 534 ((M+l) + , 100%). EXAMPLE 7 5-r((2R*.3R*)-3-((3.5-Bis(trifluoromethyl)phenyl) methyloxy)-2-phenylpiperidino}methyl " ltetrazole The compound of Description 5 (l.Og), triethylamine hydrochloride (467mg) and sodium azide (441mg) were dissolved in l-methyl-2-pyrroHdinone (5ml) and the reaction mixture was heated at reflux under nitrogen for 2h. The mixture was then cooled, and diluted with ice water (80ml) and addified to pH = 2 with methanoHc hydrogen chloride. This predpitated the product as a white sohd, which was purified on siHca using a gradient elution of methanol in dichloromethane (0-5%). The product was recrystalHsed from ether-hexane: mp 114-115°C. iH NMR (360MHz, DMSO-d 6 ) d 1.59-1.65 (2H, m, NCH 2 CH 2 CH 2 ), 2.02-2.22 (2H, m, NCH 2 CH 2 ), 2.39-2.46 (IH, m, CHHN), 2.98-3.02 (IH, m, CHHN), 3.62 (IH, s, NCHCHO), 3.66 (IH, s, NCHCHO), 3.70-3.74 (IH, d, J = 15.5Hz, NCHH-tetrazole), 4.05-4.10 (IH, d, J = 15.5Hz, NCHH-tetrazole), 4.08-4.12 (IH, d, J = 12.0Hz, OCHH), 4.51-4.54 (IH, d, J = 12.0Hz, OCHH), 5.30 (IH, s, NH), 7.30-7.35 (3H, m, ArH), 7.45-7.47 (2H, m, ArH), 7.51 (2H, s, ArH), 7.74 (IH, s, ArH); MS (CI + ) m/z 486 (M + +l, 85%). Found: C, 53.14; H, 4.58; N, 13.96. Calcd. for C 22 H 21 F β N 5 O.0.5H 2 O : C, 53.44; H, 4.48; N, 14.16%. EXAMPL S 2-rf(2R* 3R*V3-r(3.5-Bisftrifluoromethyl phenyl) methvloxvV2-phenvlpiperidino)methvll-4-methvl-1.3-thiazole Anhydrous acetone (2ml) and methanol (2ml) and tetrabutylarmnoniu perbromide (lllmg) were stirred under nitrogen to generate a solution of bromoacetone in situ. The compound of Description 6 (150mg) was added to this mixture and the resulting solution was stirred for 2h. A second equivalent of bromoacetone was added and the mixture was stirred for a further 2h. The volatile solvents were removed in vacuo and the residue was dispersed between aqueous potassium carbonate and ethyl acetate. The organic phase was washed with brine, dried (MgS0 4 ) and concentrated in vacuo affording a brown ofl. This was purified on siHca using a gradient elution of ethyl acetate in petrol (10-30%) which gave the product as a dear oil: Η NMR (360MHz, CDC1 3 ) 1.51-1.68 (2H, m, CH 2 ), 1.98-2.22 (2H, m, CH 2 ), 2.26-2.37 (IH, m, NCHH), 2.38 (3H, s, CHg), 3.18-3.26 (IH, m, NCHH), 3.47 (IH, d, J = 15.0Hz, NCHH), 3.54 (H, bs, CHO), 3.58 (H, bs, CHPh), 3.94 (IH, d, J = 15.0Hz, NCHH), 4.01 (IH, d, J = 12.5Hz, OCHH), 4.47 (IH, d, J = 12.5Hz, OCHH), 6.80 (IH, s, SCH), 7.24-7.35 (3H, m, Ar-H), 7.52-7.54 (2H, m, Ar-H), 7.58 (2H, s, Ar-H), 7.72 (IH, s, Ar-H); MS (CI + ) m z 515 (M++1, 100%). Found: C, 58.59; H, 4.88; N, 5.48 Calc for : C, 58.36; H, 4.70; N, 5.44%. EXAMPLE 9 (2R*.3R*)-3-((3.5-Bis(trifluoromethyl)phenyl)methyloxy)- l-(2-furovl)-2-phenvlpiperidine The compound of Description 1 (400mg) and triethylamine (300mg) were dissolved in dichloromethane and the mixture was stirred for 10 min at 0°C. 2-Furoyl chloride (155mg) was added to the solution and the reaction mixture was stirred for 15 min. The mixture was then washed with brine; the organic layer was separated, dried (MgS0 4 ) and concentrated in vacuo. The residue was purified by chromatography on silica using 20% ethyl acetate in petrol, affording a dear oil. Η NMR (360MHz, DMSO-d 6 ) d 1.6-1.8 (2H, m, CH 2 ), 1.9-2.1 (2H, m, CH 2 ), 2.99 (IH, mc, CHHN), 4.02 (IH, q, J = 5.0Hz, CHO), 4.0-4.2 (IH, m, CHHN), 4.78 (IH, d, J = 13.0Hz, OCHH), 4.86 (IH, d, J = 13.0Hz, OCHH), 5.95 (IH, s, CHPh), 6.62 (IH, s, furan-H), 6.99 (IH, s, furan-H), 7.25-7.36 (3H, m, ArH), 7.51-7.54 (2H, m, ArH), 7.83 (IH, s, furan-H), 7.90 (2H, s, ArH), 7.99 (IH, s, ArH); MS (CI + ) m/z 498 (M++1, 20%). EXAMPLE 10 2-r!(2R*.3R*)-3-((3.5-Bis(trifluoromethyl)phenyl) methyloxy)-2-phenylpiperidino)methyllfuran The compound of Example 9 (340mg) was dissolved in tetrahydrofuran. To this solution was added borane-dimethyl sulfide complex (0.18ml of 10M solution) and the resulting solution was heated at reflux for 8h. The mixture was cooled, methanol added to quench excess borane, and the solvents were removed in vacuo. The residue was dissolved in methanol (10ml) and potassium carbonate was added (238mg). This mixture was heated at reflux for 1 hour; the methanol was removed in vacuo and the residue was dispersed between ethyl acetate and brine. The ethyl acetate layer was dried (MgS0 4 ) and evaporated. The residue was purified by d romatography on siHca using 10% ethyl acetate in petrol. The product was recrystalHsed from ether-hexane: mp 103-104°C. L H NMR d 1.4-1.5 (2H, m, CH 2 CH 2 ), 1.8-1.9 (IH, m, CHHCH 2 N), 2.1-2.2 (2H, m, CHHCH jj and CHHN), 2.95-3.0 (IH, m, CHHN), 3.11-3.15 (IH, d, J = 15.0Hz, NCHH-furan), 3.38 (IH, s, NCHCHO), 3.54-3.58 (IH, d, J = 15.0Hz, NCHH-furan), 3.56 (IH, s, NCHCHO), 4.02-4.06 OH, d, J = 13.0Hz, OCHH-), 4.59-4.62 (IH, d, J = 13.0Hz, OCHH-), 6.08-6.09 (IH, m, furan H), 6.35-6.36 (IH, m, furan-H), 7.24-7.32 (3H, m, ArH), 7.46-7.48 (2H, m, ArH), 7.55 (IH, s, furan-H), 7.68 (2H, s, ArH), 7.93 (IH, s, ArH); MS (CI + ) m/z 485 (M++1, 100%). Found: C,_ 62.11; H, 4.80; N, 2.90. Calcd. for C, 62.27; H, 4.83; N, 2.96. EXAMPLE 11 5-rf(2R*.3R*)-3-((3.5-Bis(trifluoromethvLphenyl) methvloxvV2-phenvlpiperidino)methvl1-3-bromo-1.2.4-oxadiazol e hydrochloride Diisopropylethylamine (220μl) was added to a stirred suspension of the compound of Description 1 (200mg) and 5-bromo-3-(chloromethyl)-l,2,4-oxadiazole (99mg) (J. Heterocy ic Chem. 1989, 2β, 23) in dry acetonitrile. The resulting solution was allowed to stir at room temperature for 48 hrs. After this time the solvent was removed under reduced pressure and the residual oU purified by column chromatography on siHca using ethyl acetate in hexane (20%) as eluant to afford a waxy sohd. Treatment of an ethereal solution of this sohd with ethereal hydrogen chloride yielded a white predpitate. RecrystalHsation from ether afforded the title compound as an amorphous white sohd: mp 100-102°C. -Η. NMR (360MHz, DMSO-d 6 ) d 1.67-1.70 (2H, m, CH 2 ), 1.83 (IH, m, CHH), 2.30 (IH, m, CHH), 2.74 (IH, m, CHHN), 3.10 (IH, m, CHHN), 3.70 (IH, d, J = 11.0Hz, CH-OCH 2 ), 3.82 (IH, brs, N-CH-Ph), 4.34 (IH, d, J = 16.0Hz, NCHH-oxadiazole), 4.36 (IH, d, J = 11.0Hz, OCHH-Ar), 4.58 (IH, d, J = 16.0Hz, NCHH-oxadiazole), 4.73 (IH, d, J = 11.0Hz, OCHH-Ar), 7.34-7.42 (5H, m, ArH), 7.68 (2H, s, ArH), 7.73 (IH, s, ArH); MS (CI + ) m/z 564 ((M+l) + , 20%). Found: C, 45.64; H, 3.63; N, 6.70. Calcd. for C 23 H 20 N 3 O 2 F 6 Br.HCl: C, 45.98; H, 3.52; N, 6.99%. EXAMPLE 13 ^-r ∑^^R^-^-qg^^-Bi^ ri^μQrQmg hYD hghYl) methvloxv)-2-phenvlpiperidino)methvn-3-dimethvlamino-1.2.4- oxadiazole hydrochloride The compound of Example 11 (169mg) in dimethylamine (33% in ethanol) was heated to 40°C for 30 min. " The solvent was removed under reduced pressure and the residue purified by column chromatography on siHca using ethyl acetate in hexane (20%) as eluant. The compoτmd was dissolved in ether and treated with excess ethereal hydrogen chloride to afford a white predpitate. RecrystalHsation from ether afforded the product as white powder (llOmg): mp 179-180°C. Η NMR (360MHz, DMSO-d 6 ) d 1.59 (2H, m, CH 2 ), 2.1-2.21 (2H, m, CH 2 ), 2.4-2.45 (IH, m, CHHN), 3.01 (6H, s, N(CHβ) 2 ), 3-10 (IH, m, CHHN), 3.60 (IH, brs, CH-0-CH 2 ), 3.70 (IH, d, J = 16.0Hz, NCHH-oxadiazole), 3.78 (IH, d, J = 1.0Hz, N-CH-Ph), 3.82 (IH, d, J = 16.0Hz, NCHH-oxadiazole), 4.01 (IH, d, J = 15.0Hz, O-CHH-Ar), 4.49 (IH, d, J = 15.0Hz, O-CHH-Ar), 7.3 (3H, m, ArH), 7.4 (2H, m, ArH), 7.49 (2H, s, ArH), 7.64 (IH, s, ArH); MS (C ) m/z (M++1) 529. Found: C, 51.87; H, 4.93; N, 9.62. Calcd. for C 25 H 26 N 4 O 2 F 6 .HCl.H2O. C, 51.51; H, 5.01; N, 9.61%. EXAMPLE 13 (2R*.3R* -3-f(3.5-Bis(trifluoromethyl)phenyl)methyloxy)- 2-phenvl-l-(2-thienovLpiperidine The compound of Description 1 was reacted with 2-thiophenecarbonyl chloride as outlined in Example 9. The oil obtained after work-up and removal of solvent was purified by chromatography on siHca, eluting with 10% ethyl acetate in petroleum ether to afford the pure product as a dear ofl. VB. NMR (250MHz, CDC1 3 ) d 1.6-1.8 (2H, m, CH 2 ), 2.1-2.2 (2H, m, CH 2 ), 3.0 (IH, m, CHN), 4.0 (IH, dt, J = 5Hz, 2Hz, CH), 4.1 (IH, brs, CHN), 4.7 (IH, d, J = 7Hz, CHAr), 4.8 (IH, d, J = 7Hz, CHAr), 6.2 (IH, brs, NCHPh), 7.02 (IH, dd, J = 1, 2Hz, thiophene-H), 7.3-7.44 (4H, m, Ar-H), 7.5 (IH, dd, J = 1, 3Hz, thiophene-H), 7.6-7.92 (5H, m, Ar-H). EXAMPLE 14 (2R*.3R*V3-((3.5-Bis(trifluoromethyl phenyl)methyloxy)- 2-phenvl-l-(2-thienvlmethvl'.piperidine The compound of Example 13 was reacted with borane dimethylsulfide as described in Example 10. The free base was recrystalHsed from ether and hexane to give the product as a white crystalline sohd. *H NMR (250MHz, CDC1 3 ) d 1.44-1.64 (2H, m, CH 2 ), 1.9-2.2 (2H, m, CH 2 ), 2.24 (IH, d, J = 7Hz, CHN), 3.14 (IH, d, J = 7Hz, CHN), 3.4 (IH, s, CHO), 3.56 (IH, s, NCHPh), 3.6 (IH, s, CH-thiophene), 4.88 (IH, d, J = lOHz, CH-thiophene), 4.0 (IH, d, J = lOHz, CHAr), 4.24 (IH, d, J = 10Hz, CHAr), 6.7 (IH, d, J = 1Hz, thiophene-H), 6.9 (H, dd, J * 2Hz, 3Hz, thiophene-H), 7.2 (IH, d, J = 3Hz, thiophene-H), 7.28 (4H, m, Ar-H), 7.5 (3H, m, Ar-H), 7.68 (IH, s, Ar-H). MS m/z 500 (M+, 100%). EXAMPLE 15 <vrf(2R » .3R*V3-((3.fi- i B ftri lιιormtιethvl^henvn ' methvloxvV2-phenvlpiperidinolmethvn-2.3-dihvQro-4-methvl-3- thipsp-l- ,4- ria3Qte hγdrQchlQride A suspension of the compound of Description 7 (0.50g) and methyl isothiocyanate (0.09ml) in 1-butanol (10ml) was heated under reflux for 10 min. l,8-Diazabicyclo[5.4.0]undec-7-ene (0.1ml) was added and the reaction mixture was heated under reflux for 2.5h. The solvent was removed in vacuo and the residue was partitioned between water and ethyl acetate. The organic layer was dried (MgS0 4 ) and evaporated. The residue was purified on siHca using 5% methanol in dichloromethane as eluant to give the title compound. The product (470mg) was characterised as the hydrochloride salt. Η NMR (360MHz, DMSO-d 6 ) d 1.77-1.93 (2H, m, CH 2 ), 2.05-2.22 (IH, m, CHH), 2.31 (IH, d, J -= 13.5Hz, CHH), 3.42 (3H, s, CH 3 ), 3.45-3.51 (IH, m, NCHHCH 2 ), 3.83 (IH, d, J = 12.0Hz, NCHHCH 2 ), 3.97 (IH, brs, CHO), 4.24 (IH, d, J = 15.5Hz, N-CHH-het), 4.32 (IH, d, J = 15.5Hz, N-CHH-het), 4.33 (IH, d, J = 12.5Hz, O-CHH), 4.76 (IH, s, NCH), 4.80 (IH, d, J = 12.5Hz, O-CHH), 7.42-7.50 (3H, m, ArH), 7.59 (2H, brs, ArH), 7.85 (2H, s, ArH), 7.89 (IH, s, ArH), 9.15 (IH, brs, NH); MS (FAB) m/z 530 ((M+l) + , 13%). EXAMPLE 16 3-rf(2R*-3R*%3-((3.5-Bi S (trifluoromethvl phenvn methvloxvV2-phenvlpiperidino}methvl1-1.2.4-triazole The compound of Description 1 (l.Og), anhydrous potassium carbonate (0.94g) and N-formyl-2- chloroacetamidohydrazone (0.46g), (prepared according to Yanagisawa, L, J. Med. Chem. 1984, 2L 849) were heated to 60°C in anhydrous dimethylformamide for 3h, foUowed by heating at 130°C for 12h. The reaction mixture was cooled, diluted with ethyl acetate (100ml) and washed with water, (3 x 20ml). The ethyl acetate layer was dried (MgS0 4 ), filtered and evaporated to give a brown oU. This was purified on siHca using ethyl acetate in petrol (70:30) as eluant. This afforded the product as a white soHd. NMR (250MHz, CDC1 3 ) d 1.6 (2H, m, CH 2 ), 1.95-2.24 (2H, m, CH 2 ), 2.34 (IH, m, NCHH), 3.06 (IH, m, NCHH), 3.44 (IH, d, NCHH-triazole), 3.5 (IH, bs, CHO), 3.6 (IH, bs, NCHPh), 3.8 (IH, d, N-CHH-triazole), 4.04 (IH, d, OCHH-Ar), 4.50 (IH, d, OCHHAr), 7.3 (3H, m, ArH), 7.44 (2H, m, ArH), 7.5 (2H, s, ArH), 7.7 (IH, s, ArH), 7.9 (IH, s, triazole-H). MS (CT+) m/z 485 (M++1, 35%). EXAMPLE 17 5-r((2R*.3R*)-3-fr3.5-Bi S (trifluorom e thvl)ph 6 nvl) methvloxv)-2-phenvlpiperidino)methvll-2.3-dihvdro-(4H)-3- thioxo-1.2.4-triazole The compound of Description 7, potassium thiocyanate (0.45g) and cone, hydrochloric add (2.3ml) in water (12ml) were heated under reflux for 2h. After cooling, solid sodium hydroxide was added until pH = 8 and the aqueous layer was extracted with ethyl acetate. The organic layer was dried (MgS0 4 ), filtered and evaporated to give the crude semi-carbazide which was heated at reflux in 2N sodium hydroxide solution (10ml) for 2h. After cooling the solution was aridified to pH 5-6 and the product extracted into ethyl acetate. The organic layer was dried (MgS0 4 ), filtered and evaporated. The crude triazole was chromatographed on sUica eluting with 40% ethyl acetate 60-80 petroleum ether to give the title compound as a white sohd. Η NMR (250MHz, CDC1 3 ) d 1.6 (2H, m, CH 2 ), 1.9-2.3 (3H, m, CH 2 + NCHH), 2.95 (IH, bd, NCHH), 3.16 (IH, d, N-CHH-Het), 3.20 (IH, bs, CHO), 3.6 (IH, bs, NCHPh), 3.78 (IH, d, N-CHH-Het), 4.1 (IH, d, CHH-Ar), 4.58 (IH, d, CHH-Ar), 7.32 (5H, m, ArH), 7.5 (2H, s, Ar-H), 7.78 (IH, s, ArH). MS (FAB) m/z 517 (M + +l, 80%). EXAMPLE 18 5-rf(2R*.3R*)-3-((3.5-Bis(trifluoromethvDphenvD methyloxy)-2-phenylpiperidino}methyl1-2-methyltetrazole The compound of Example 7 (500mg) was suspended in water (4ml) and sodium hydroxide (44mg) added. This was heated to an external temperature of 96°C and dimethyl sulphate (65mg) added. The reaction mixture was aUowed to stir under nitrogen at 96°C for lh after which time stirring was continued for 24h at 5°C. After this time, the product was extracted into dichloromethane and washed with water and brine. The organic layer was dried (MgS0 4 ) and evaporated. The residue was purified on siHca using medium pressure chromatography (Lobar), and eluted with 25% ethyl acetate in petrol. The first compound to be eluted was isolated, and this afforded the product (50mg) as a crystalline sohd, which was recrystaUised from ether/hexane to afford white crystals: mp 139-141°C. NMR (360MHz, DMSO) d 1.44-1.51 (2H, m, CH 2 ), 1.79-1.82 (IH, m, CHH), 2.12-2.15 (IH, m, CHH), 2.19-2.25 (IH, m, CHHN), 2.97-3.00 (IH, m, CHHN), 3.37 (IH, d, J = MHz, N-CHH-tetrazole), 3.52 (IH, s, NCHCHO), 3.58 (IH, s, NCHCHO), 3.81 (IH, d, J = MHz, N-CHH-tetrazole), 4.03 (IH, d, J = 13Hz, OCHH), 4.31 (3H, s, CHg), 4.60 (IH, d, J = 13Hz, OCHH), 7.23-7.33 (3H, m, ArH), 7.49-7.51 (2H, m, ArH), 7.68 (2H, s, ArH), 7.93 (IH, s, ArH); MS (CI + ) m/z δOO ((M+l) + , 100%). Found: C, δδ.δβ; H, 4.76; N, 14.20. Calculated for CagHjjgNjiOFβ: C, δδ.31; H, 4.64; N, 14.02%. EXAMPLE 19 5-r{(2^*,3fi*)-3-((3,5-Big(triflμQrpm^hγl)phgnyl) methyloxy)-2-phenylpiperidino}methvn-l-methyltetrazole The title compound was prepared as described in Example 18. During purification, the second compound to be eluted was isolated, and this afforded the product (120mg) as a crystalline sohd, which was recrystaUised from ether/hexane to afford yeUow crystals: mp 75-77°C. Η NMR (360MHz, DMSO) d 1.51-1.55 (2H, m, CH 2 ), 1.84-1.87 (IH, m, CHH), 2.12-2.16 (IH, m, CHH), 2.31-2.37 (IH, m, CHHN), 2.81-2.84 (IH, m, CHHN), 3.52 (IH, d, J = 15Hz, NCHH-tet), 3.δ4 (IH, s, NCHCHO), 3.60 (IH, s, NCHCHO), 3.82 (IH, d, J = MHz, NCHH-tet), 3.84 (3H, s, CH 3 ), 4.14 (IH, d, J = 13Hz, OCHH), 4.85 (IH, d, J = 13Hz, OCHH), 7.26-7.32 (3H, m, ArH), 7.45-7.48 (2H, m, ArH), 7.74 (2H, s, ArH), 7.94 (IH, s, ArH); MS (CI + ) m/z 500 ((M+l) + , 20%). 10 EXAMPLE gO 3-r((2R*.3R*V3-((3.5-Bis(trifluoromethyl)phenyl) methyloxy)-2-phenylpiperidinolmethvn-δ-dimethylamino-1.2.4- thiadiazole lδ a) δ-Dimethylamino-3-(chloromethyl)-1.2.4-thiadiazole A solution of dimethylamine in ethanol (0.5ml x 33%) was added to a stirred suspension of δ-chloro-3-(chloromethyl)- 1,2,4-thiadiazole (δ40mg) (J. Goerdeler, Chem. Ber. 19δ7, 20, p 182 or ICI EP 0006679) and potassium carbonate (l.Og) in 20 methanol. The solution was stirred at room temperature for three hours, and then the solvent removed under reduced pressure. The residue was taken up in ethyl acetate (40ml), washed with water (20ml) and brine (20ml). The organic layers were dried (MgS0 4 ), filtered and the solvent removed to afford a 2δ yeUow gum. Flash chromatography using 10% ethyl acetate in hexane as eluent, afforded the product as a yellow oil (330mg). Η NMR (360MHz, CDC1 3 ) d 3.15 (6H, s, NCCHa - 51 ( 2H > s » C1-CH 2 ); MS (CI + ) m/z 178 ((M+l) + , 95%). b) A solution of the compound of Description 1 (223mg), 30 5-dimethylamino-3-(chloromethyl)-l,2,4-thiadiazole (lOOmg) and dnsopropylethylamine (0.2ml) were heated at reflux in dry acetonitrile for three hours. The reaction was then aUowed to cool to room temperature and the solvent removed under reduced pressure. Purification of the residue by flash δ chromatography (40% EtOAc/nHex) gave a yeUow gum. RecrystalHsation from n-hexane afforded the product as yeUow plates: mp 144-14δ°C. X H NMR (360MHz, CDC1 3 ) d l.δ7 (2H, m, CH 2 ), 2.11 (3H, m, CH 2 +CHH), 2.42 (IH, m, CHH), 3.11 (6H, s, N CH 3 ) 2 ), 3.20 (IH, m, CH-OCH 2 ), 3.47 (IH, d, J = 14.5Hz, 10 CHH-thiadiazole), 3.56 (IH, m, CHPh), 3.75 (IH, d, J = 14.5Hz, CHH-thiadiazole), 4.03 (IH, d, J = 10.5Hz, OCHH-Ar), 4.45 (IH, d, J = 10.5Hz x OCHH-Ar), 7.30 (3H, m, ArH), 7.δl (2H, s, ArH), 7.δ3 (2H, m, ArH), 7.69 (IH, s, ArH); MS (CI + ) m/z δ4δ ((M+l) + , 60%). Found: C, δδ.12; H, 4.7δ; N, 10.38. Calcd. for lδ C 25 H 20 F 6 N 4 SO: C, δδ.M; H, 4.81; N, 10.30%. EXAMPLE 21 2-rfr2R*.3R*)-3-f(3.5-Bis(trifluoromethyl)phenyl methyloxy)-2-phenylpiperidino}methvn-4.7-dimethylbenzoxazole 20 A solution of 2-(chloromethyl)-4,7-dimethylbenzoxazole (28δmg) in dry acetonitrile (10ml) was added to a solution ofthe compound of Description 1 in dry acetonitrile (10ml) containing dnsopropylethylamine (0.4ml). The resulting mixture was heated at reflux for three hours, cooled to room temperature and 2δ the residue purified by flash diromatography on siHca gel using 20% ethyl acetate/n-hexane as eluant. RecrystalHsation of the isolated material from n-hexane afforded the product as white needles: mp 109-110°C. Η NMR (CDC1 3 ) 1.49-1.53 (2H, m, CH 2 ), 1.56-1.60 (IH, m, CHH), 2.03-2.09 (IH, m, CHH), 30 2.10-2.16 (IH, m, CHHN), 2.36-2.40 (IH, m, CHHN), 2.47 (3H, s, Ar-CHg), 2.δ4 (3H, s, ArCHa), 3.24 (IH, m, CHN), 3.δ9 (IH, m, CHOCH 2 ), 3.67 (IH, d, J = 12.0Hz, N-CHH-benzoxazole), 3.79 (IH, d, J = 12.0Hz, N-CHH-benzoxazole), 3.96 (IH, d, J = 10.0Hz, OCHH), 4.47 (IH, d, J = 10.0Hz, OCHH), 6.99 (2H, s, δ ArH), 7.32 (3H, m, ArH), 7.δ4 (2H, s, ArH), 7.δ7 (2H, m, ArH), 7.71 (IH, s, ArH); MS (CI + ) m/z δ63 ((M+l) + , 70%). Found: C, 64.09; H, δ.04; N, δ.12. Calcd for C 30 H 28 N 2 O 2 F 6 : C, 64.0δ; H, δ.01; N, δ.00%. 0 EXAMPLE 22 2-r((2R*.3R*V3-((3.5-Bis(trifluoromethyl.phenvD methyloxy)-2-phenylpiperidinolmethvnbenzoxazole This compound was prepared foUowing the procedure described in Example 21, using 2-(chloromethyl)benzoxazole as 5 the alkylating agent: mp 9δ-97°C. Η NMR (CDC1 3 ) d 1.47-1.60 (2H, m, CH 2 ), 2.06-2.19 (2H, m, CH 2 ), 2.42-2.56 (IH, dd, IH, J = 6.0, 4.0Hz, NCHH), 3.26 (IH, dd, J = 4.0, 2.0Hz, NCHH), 3.61 (IH, s, CHO), 3.66 (IH, d, J = 15.0Hz, NCΗH-benzoxazole), 3.66 (IH, d, J = 2.0Hz, CHPh), 4.02 (IH, d, J = 15.0Hz, 0 CHH-benzoxazole), 4.04 (IH, d, J = 12.0Hz, OCHH), 4.48 (IH, d, J = 12.0Hz, OCHH), 7.26-7.67 (12H, m, ArH); MS (CI + ) m/z 53δ ((M+l) + 65%). Found: C, 62.36; H, 4.67; N, 5.27. Calc for C, 62.39; H, 4.58; N, 5.20%. 5 EXAMPLE 23 4-r{(2S.3S)-3-((3.5-Bis(trifluoromethyl)phenyl)methyloxy)- 2-phenylpiperidinolmethyl " loxazole l,3-oxazole-4-carboxaldehyde was prepared foUowing the procedure described by J. Hodges, W. Patt and C. ConnoUy, J. Ory. Chem. 1991, fifi, 449-452. a) 4-(Hvdroxvmethvl ' )-1.3-oxazole l,3-Oxazole-4-carboxaldehyde (0.38g) was dissolved in anhydrous methanol and stirred under nitrogen; sodium borohydride (0.074g) was added carefully. After 1 hour no starting material was present by TLC using 50% ethyl acetate in hexane as eluent. The methanol was removed by rotary evaporator (water bath temp 40°C). The residue was purified by chromatography on siHca eluting with 100% diethyl ether. This afforded the alcohol (0.27g) as a white sohd. L H NMR d (360 MHz, CDC1 3 ) 2.93 (OH), 4.63 (2H, s, CH 2 OH), 7.64 (IH, s, oxazole-H), 7.90 (IH, s, oxazole-H). b) 4-rf(2S.3SV3-((3.5-BisftrifluoromethylYphenvD methvloxvι-2-phenvlpiperidinolmethvrioxazole 4r(Hydroxymethyl)-l,3-oxazole (0.13g) was dissolved in anhydrous dichloromethane (4ml) under an atmosphere of nitrogen. Triethylamine (0.19ml) and p-toluenesulfonyl chloride (0.13g) were added to the reaction mixture which was stirred for 1 hour at room temperature. A further portion of p-toluenesulfonyl chloride (0.13g) and a catalytic amount of dimethylaminopyridine were added to the reaction mixture. The compound of Description 3 (1.2g, free base) was dissolved in dimethylformamide (δml) and was added to the reaction mixture foUowed by triethylamine (0.19ml). The mixture was heated at 60°C for 2h and the resulting mixture was d luted with water (δOml) and extracted with dichloromethane (3 x 20ml). The combined organic layers were dried (MgS0 4 ) and concentrated in vacuo to afford a yeUow oil. This was purified by chromatography on siHca gel using a gradient elution of 30-60% ether in hexane to afford the title compound as a white solid. This was recrystaUised from ether/hexane: mp 102-104°C. Η NMR (360MHz, CDC1 3 ) d 1.46-1.64 (IH, m, NCH 2 CH 2 CHH), δ 1.7-1.87 (IH, m, NCH 2 CH 2 CHH), 1.96-2.20 (2H, m, NCH 2 CH 2 ), 2.32-2.48 (IH, m, NCHH), 3.20-3.46 (3H, m, NCHH + NCHH-oxazole + CHOOE j Ar), 3.δδ (IH, brs, CHPh), 3.68 (IH, d, J = M.δHz, NCHH-oxazole), 4.01 (IH, d, J = ll.δHz, OCHHAr), 4.46 (IH, d, J = ll.δHz, OCHHAr), 7.24-7.δ8 (8H, m, 0 ArH), 7.70 (IH, s, ArH), 7.80 (IH, s, ArH); MS (CI + ) 48δ (M+ + 1, 100%) EXAMPLE 24 2-rf(2S.3S)-3-((3.5-Bis(trifluoromethyl phenyl)methyloxy)- 5 2-phenvlpiperidino)methvnpvrazine a) 2-(Chloromethvl>pvrazine 2-Methylpyrazine (lg) was dissolved in carbon tetrachloride (50ml) under nitrogen. N-Chlorosucdnimide (1.42g) and benzoyl peroxide (δOmg) were added and the 0 mixture was heated at reflux for 24h. The reaction mixture was cooled and filtered through ceHte and the filtrate was concentrated in vacuo. The resulting oil was purified on siHca using 30% ethyl acetate in petrol. Η NMR (360MHz, CDC1 3 ) d 4.72 (2H, s, CH 2 C1), 8.δ6 (2H, s, ArH), 8.76 (IH, s, ArH). δ b) 2-r(f2S.3SV3-((3.5-Bi S (trifluoromethvl phenvl) methyloxy)-2-phenylpiperidino)methyl1pyrazine 2-(Chloromethyl)pyrazine (0.17g), potassium carbonate (0.6g) and the compound of Description 3 (0.3δg) were suspended in dimethylformamide (3ml); the reaction mixture 0 was heated at 60°C for 12h. The mixture was cooled, diluted with water (30ml) and extracted with ethyl acetate (2 x 20ml). The combined organic layers were washed with brine, dried (MgS0 4 ) and concentrated in vacuo to afford a brown oU. The product was purified by column chromatography on siHca gel δ using a gradient elution of lδ-35% ethyl acetate in hexane. This afforded the product as a white soHd, which was recrystaUised from pentane to give colourless crystals: mp 108-110°C . X H NMR (360MHz, DMSO-dβ) d 1.42-1.60 (2H, m NCH 2 CH 2 CH 2 ), 1.77-1.92 (IH, m, NCH 2 CHH), 2.13-2.25 (2H, m, NCHH + 10 NCH 2 CHH), 2.84-2.92 (IH, m, NCHH), 3.12 (IH, d, J = M.OHz, NCHH-pyrazine), 3.5δ (IH, m, CHO), 3.63 (IH, m, CHPh), 3.78 (IH, d, 14.0Hz, NCHH-pyrazine), 4.11 (IH, d, J = 13.0Hz, OCHHAr), 4.64 (IH, d, J = 13.0Hz, OCHHAr), 7.20-7.33 (3H, m, ArH), 7.49-7.δ6 (2H, m, ArH), 7.71 (2H, s, ArH), 7.93 (IH, s, lδ ArH), 8.48-8.63 (3H, m, ArH); MS (CU) 496 (M++1, 60%). Found: C, 60.90; H, 4.86; N, 8.48. Calcd. for C, 60.60; H, 4.68; N, 8.48%. EXAMPLE 2$ 20 4-rf(2S.3SV3-((3.5-Bisrtrifluoromethv phenyl)methyloxy)- 2-phenvlpiperidinolmethvll-2-methvl-1.3-thiazolium dihydr chlpride 4-(Chloromethyl)-2-methylthiazole hydrochloride (83mg) was added to a suspension ofthe compound of Description 3 and 25 potassium carbonate in dimethylformamide (5ml). The resulting mixture was heated at 60°C for 18h, cooled to room temperature and diluted with water (50ml). This solution was extracted with ethyl acetate (2 x 25ml) and the combined organic extracts were washed with water (2 x 20ml), brine 30 (20ml), dried (MgS0 4 ) and filtered. The resulting solution was evaporated under reduced pressure to afford a yellow oil. This was purified by medium pressure liquid chromatography using 50% ethyl acetate in hexane to afford the product as a white sohd. This was treated with ethereal hydrogen chloride and δ recrystaUised from methyl-έ-butyl ether to afford the title compound: mp δ8-60°C. Η NMR (360MHz, DMSO-d 6 ) d 1.71 (2H, m, CH 2 ), 2.11 (2H, mc, CH 2 ), 2.49 (IH, m, CHHN), 2.69 (3H, s, Ar-CHa), 3.1δ (IH, m, CHHN), 3.δ4 (IH, m, CHO), 4.12 (2H, m, CH 2 -thiazole), 4.16 (IH, d, J = 10.0Hz, OCHHAr), 4.δ8 0 (IH, brs, CHPh), 4.76 (IH, d, J = 10.0Hz, OCHHAr), 7.40-7.43 (δH, m, ArH), 7.64 (IH, brs, ArH), 7.92 (2H, s, ArH), 7.97 (IH, s, ArH); MS (CI + ) m/z 515 (M+ + 1). Found: C, 48.17; H, 4.76; N, 4.52. Calcd. for C 25 H 24 F 6 N 2 OS.2HCl.2H 2 O: C, 48.16; H, 4.85; N, 4.49%. 5 EXAMPLE 26 3-r((2S.3S)-3-((3.δ-Bis(trifluoromethyl phenyl)methyloxy)- 2-phenylpiperidino}methvn-1.2.4-oxadiazole hydrochloride 3-(Chloromethyl)-l,2,4-oxadiazole (270mg) was added to a 0 rapidly stirred suspension of the compound of Description 3 and potassium carbonate in dimethylformamide (10ml). The reaction mixture heated at 60°C for 4h, cooled to room temperature and dUuted with water (δOml). The aqueous solution was extracted with ethyl acetate (3 x 50ml) and the δ organic extracts were combined, washed with water (3 x δOml), brine (δOml), dried (MgS0 4 ) and filtered. The resulting solution was concentrated under reduced pressure and purified by column chromatography on siHca gel using 20% ethyl acetate in hexane as eluent. The resulting oil was treated with ethereal 0 hydrogen chloride to afford the title compound as a white powder: mp 74-7δ°C. H NMR (360MHz, DMSO-d 6 ) d 1.62 (2H, m, CH 2 ), 1.97-2.1 (2H, m, CH 2 ), 2.δ0 (IH, m, CHHN), 3.16 (IH, m, CHHN), 3.δl (IH, m, CHO), 3.69-3.72 (3H, m, CH 2 -oxadiazole + CHPh), 4.14 (IH, d, J = 10.0Hz, OCHHAr), δ 4.70 (IH, d, J = 10.0Hz, OCHHAr), 7.32 (3H, m, ArH), 7.4δ (2H, m, ArH), 7.78 (3H, m, ArH), 7.94 (IH, s, ArH). EXAMPLE 27 3-rf(2S.3S)-3-r(3.5-Bisrtrifluoromethyl)phenyl methyloxyV 10 2-phenvlpiperidino)methvll-δ-iodo-1.2.4-thiadiazole a) 5-Iodo-3-(iodomethyl)-1.2.4-thiadiazole Sodium iodide (excess) was added to a stirred solution of 5-cHoro-3-(cMoromethyl)-l,2,4-thiadiazole (3.0g) (J. Goerdeler, Chem. Ber. 19δ7, 20, 182) in dry butanone (lδml). The lδ resulting solution was heated at reflux for four hours, cooled to room temperature and filtered. The filtrate was dfluted with water (20ml) and extracted with ethyl acetate (δOml). The ethyl acetate layer was dried (MgS0 4 ), filtered and concentrated in vacuo to afford a red oU, which was used in the foUowing 20 reaction without further purification. b) 3-rf(2S.3S -3-((3.δ-Bis(trifluoromethyl)phenvD methyloxyl-Σ- phenylpiperidinolmethyn-δ-iodo-l^^-thiadiazole Dnsopropylethylamine (116mg) was added to a stirred solution of δ-iodo-3-(iodomethyl)-l,2,4,thiadiazoIe (160mg) and 2δ the compound of Description 3 (200mg) in dry acetonitrile (10ml). The resulting solution was stirred at room temperature for 18h. The reaction mixture was filtered and the solvent was removed in vacuo to afford a red oU. This was purified using column chromatography on siHca gel using 20% ethyl acetate in 30 hexane as eluent. This afforded the product as a powder: mp 98-101°C. NMR (360MHz, CDC1 3 ) d l.δδ (3H, m, NCH 2 CH 2 CH 2 + NCH 2 CHH), 2.13 (2H, m, NCH 2 CHH + NCHH), 2.42 (IH, m, CHHN, 3.21 (IH, m, CHO), 3.69 (2H, m, CHPh + CHH-thiadiazole), 4.02 (2H, m, CHH-thiadiazole + OCHH), 4.48 δ (IH, d, J = 8.0Hz, OCHH), 7.32 (δH, m ArH), 7.51 (2H, s ArH), 7.70 (IH, s, ArH). EXAMPLE 28 3-rf(2S.3SV3-((3.5-Bisftrifluoromethvl)phenvlιmethvloxv)- 10 2-phenvlpiperidinolmethvn-1.2.4-thiadiazole hydrochloride Sodium borohydride (280mg) was added to a stirred solution of the compound of Example 27 (δOOmg) and paUadium (II) chloride (280mg) in dry methanol (2δml). The resulting mixture was stirred for 30 min and then filtered through celite; lδ the filtrate was concentrated in vacuo. The solid residue thus obtained was dissolved in ethyl acetate and the solution was washed with water (10ml), the organic extract was dried (MgS0 4 ), filtered and concentrated in vacuo to afford a yeUow ofl. Treatment of this oil with ethereal hydrogen chloride 20 afforded the title compound as a white powder: mp 89-90°C. X H NMR (360MHz, DMSO-oV d 1.79 (2H, m, CH 2 ), 1.9-2.20 (3H, m, CHHN + NCH 2 CH 2 ), 2.6 (IH, m, CHHN), 3.8 (IH, bm, CHO), 3.89 (IH, brs, CHPh), 4.2-4.3 (3H, m, CH 2 -thiadiazole + OCHH), 4.76 (IH, d, J = 9.0Hz, OCHH), 7.39 (3H, m, ArH), 7.δδ (2H, m, 25 ArH), 7.89 (2H, s, ArH), 8.32 (IH, s, ArH), 10.32 (IH, s, N-CH-S); MS (CI + ) m/z 502 (M + + l). Found: C, 49.31; H, 4.09; N, 7.18%. Calcd. for C 23 H 21 F 6 N 3 OS.HC1.1.25H 2 0 : C, 49.48; H, 4.37; N, 7.δ2%. EXAMPLE 29 3-rf(2S,3S)-3-((3,5-Sis(trifluprpmethyl)phepγl)mgt γIp?sγ)- 2-phenvlpiperidinolmethvl1-5-methoχy-1.2.4-thiadiazole hy r chl ri 5 Sodium methoxide (34mg) was added to a stirred solution of he compound of Example 27 (200mg) in methanol (5ml). The solution was heated at reflux for 2h, cooled to room temperature and the solvent removed under reduced pressure affording a soHd residue. The sohd was dissolved in ethyl acetate (lδml), 10 and the organic phase was washed with water (20ml), separated, dried (MgS0 4 ) and the solvent was removed under reduced pressure. The residual soHd was treated with ethereal hydrogen chloride and the resulting soHd was recrystaUised from ethyl acetate to afford the product as white needles: mp lδ 74-7δ°C. Η NMR (360MHz, DMSO-d 6 ) d l.δδ (2H, m, CH 2 ), 1.73 (IH, m, CHH), 2.09 (2H, m CH 2 ), 2.43 (IH, m, CHH), 3.20 (IH, m, CHO), 3.49 (2H, m, CHJPh + CHH-thiadiazole), 3.7δ (IH, m, CHH-thiadiazole), 4.02 (IH, d, J = 10.0Hz, OCHH), 4.14 (3H, s, OCH 3 ), 4.4δ (IH, d, J = 10.0Hz, OCHH), 7.30 (3H, m ArH), 0 7.δl (4H, brs, ArH), 7.δ4 (IH, s, ArH); MS (CI + ) m/z δ32 (M+ + 1). Found: C, 49.89; H, 4.10; N, 7.41. Calcd. for C 24 H 23 F 6 N 3 O 2 S.HC1.0.δH 2 O: C, 49.96; H, 4.37; N, 7.28%. EXAMPLE 30 25 3-rf(2S.3SV3-(r3.δ-BisftrifluoromethvDphenvl methvloxvV 2-phenvlpiperidino>methvl1-1.2.4-triazole dihvdrochloride The title compound was prepared according to the procedure described in Example 16, using the compound of Description 3 as starting material. The free base was treated with ethereal hydrogen chloride to afford the product as a white crystalline solid: mp (free base) 209-210°C . Found: C, 49.36; H, 4.δ7; N, lO.Oδ. Calcd. for C, 49.δ6; H, δ 4.34; N, 10.0δ%. EXAMPLE 31 5-rf(2S.3S)-3-((3.5-Bis(trifluoromethyl)phenyl)methyloxy)- 2-phenvlpiperidinolmethvπ-2.3-dihvdro-(4H)-3-thioxo-1.2.4- 0 triazole hydrochloride The title compound was prepared according to the procedure described in Example 17, using the compound of Description 8 as a starting material. This afforded the product as a white solid which was treated with ethereal hydrogen 5 chloride to yield the crystalline hydrochloride: mp lδ4-157°Cr Found: C, 46.59; H, 4.52, N, 9.26; Cl, 5.84. Calcd. for C 23 H 22 F 6 N 4 O.HCl.2H 2 O: C, 46.90; H, 4.62; N, 9.51; Cl, 6.02%. EXAMPLE 32 0 2-rf(2S.3S)-3-((3.5-Bis(trifluoromethvDphenyl)methyloxy)- 2-phenylpiperidino}methyl1-l-(p-toluenesulfonyl)imidazole dihvdrochloride (a) N-(p-Toluenesulfonvl)imidazole-2-carboxaldehvde. Imidazole-2-carboxaldehyde (1.92g) was suspended in δ dichloromethane (20ml). p-Toluenesulfonyl chloride (3.8g) and triethylamine (2.8ml) were added to the mixture which was stirred at room temperature for 12 hours. The resulting slurry was d luted with water and the organic layer was washed with brine, dried (MgS0 4 ) and filtered. The dichloromethane layer was concentrated in vacuo and the residue was purified by column chromatography on siHca using 50% ethyl acetate in hexane as eluent. This afforded the product as a yeUow oU which crystaUised on standing. *H NMR (360MHz, CDC1 3 ) d 2.44 (3H, s, ArCH 3 ), 7.31 (IH, d, J=l.δHz, imidazole-H), 7.37 (2H, d, J=8.0Hz, ArH), 7.83 (IH, d, J=l.δHz, imidazole-H), 8.00 (2H, d, J=8.0Hz, ArH), 9.78 (IH, s, CHO). MS (Cl *1" ) m/z 2δl (M++1). (b) 2-fHvdroxymethylVl-(p-toluenesulfonvDimidazole The aldehyde of (a) above (3g) was dissolved in methanol (15ml) and sodium borohydride (114mg) was added portionwise. This solution was stirred for 10 min. Methanol was removed in vacuo and the residue was dispersed between ethyl acetate and water. The organic layer was separated, dried (MgS0 4 ) and filtered and the solvent was removed in vacuo to afford a crystalline soHd. Η NMR (250MHz, CDC1 3 ) d 2.42 (3H, s, ArCH 3 ), 4.84 (2H, s, CH 2 0), 7.00 (IH, d, J=-1.5Hz, imidazole-H), 7.36 (2H, d, J=8.0Hz, ArH), 7.40 (IH, d, J=1.5Hz, imidazole-H), 7.84 (2H, d, J=8.0Hz, ArH). (c) ((N-p-Toluenesulfonyl)imidazol-2-yl methyl methanesulfonate The alcohol described in (b) above (12.6mg) was dissolved in dichloromethane (2.5ml) and triethylamine (.07ml). This solution was cooled to 0°C. Methanesulfonyl chloride (.04ml) was added to the solution dropwise. After stirring for 10 wrin g the solution was diluted with water and the organic layer was separated, dried (MgS0 4 ), filtered and the solvent removed in vacuo to yield a white sohd which was used in the foUowing reaction without further purification. L H NMR (250MHz, CDC1 3 ) d 2.44 (3H, s, ArH), 2.94 (3H, s, S0 2 CH 3 ), δ.δl (2H, s, CH 2 S0 2 ), 7.08 (IH, d, J=l.δHz, imidazole-H), 7.40 (2H, d, J=8.0Hz, ArH), 7.49 (IH, d, J=l.δHz, imidazole-H), 7.92 (2H, d, J=8.0Hz, ArH). (d) ((N-p-Toluenesulfonyl)imidazol-2-yl)methylmethane- δ sulfonate (1.6g) was added to a suspension of the compound of Description 3 (2.47g) and potassium carbonate (800mg) in dimethylformamide (10ml) and the resulting mixture was heated at 100°C for 2h. The mixture was cooled, diluted with water (100ml) and extracted with ethyl acetate (3 x 20ml). The 10 organic extracts were combined, washed with brine, dried (MgS0 4 ) and concentrated in vacuo. This afforded a colourless oU which was purified by column chromatography on siHca using 2δ-30% ethyl acetate in hexane. This afforded the product as a white crystalline soHd which was recrystaUised from lδ dichloromethane/petrol: mp 12δ-126°C . Η NMR (360MHz, DMSO-d 6 ) d 1.4-1.5 (IH, m, NCH 2 CH 2 CHH), 1.5-1.67 (IH, m, NCH 2 CH 2 CHH), 1.8-2.0 (IH, m, NCH 2 CHH), 2.06-2.1 (IH, m, NCH 2 CHH), 2.35 (3H, s, CH 3 ), 2.4 (IH, mc, NCHH), 2.7-2.86 (IH, m, NCHH), 3.50 (IH, d, J = 14.0Hz, CHH-imidazole), 3.56 20 (IH, brs, CHO), 3.76 (IH, d, J = 1.5Hz, CHPh), 4.08 (IH, d, J = 14.0Hz, CHH-imidazole), 4.09 (IH, d, J = 12.0Hz, OCHH), 4.48 (IH, d, J = 12.0Hz, OCHH), 6.96 (IH, d, J = l.OHz, imidazole-H), 7.12 (2H, d, J = 8.δHz, ArH), 7.2-7.3 (3H7 m, ArH), 7.34 (IH, d, J = l.OHz, imidazole-H), 7.46-7.δ8 (2H, m, ArH), 2δ 7.60 (2H, s, ArH), 7.71 (IH, ArH), 7.79 (2H, d, J = 8.δHz, ArH); MS (CI + ) m/z 638 (M+ + 1). Found: C, δ8.48; H, 4.78; N, 6.72; S, 4.81. Calcd. for C 31 H 29 F 6 N 3 0 3 S: C, δ8.39; H, 4.δ8; N, 6.δ9; S, δ.03%. 30 EXAMPLE 33 2-rf2S.3S)-3-((3.5-Bisftrifluoromethyl>phenvDmethyloxy- 2-phenylpiperidinolmethyllimidazole dihvdrochloride The compound of Example 32 was dissolved in δ dichloromethane and ethereal hydrogen chloride was added. The resulting solution was stirred for 30 minutes whereupon the title compound crystalHsed from solution. This was removed by filtration and recrystaUised from ethyl acetate/metiianol to afford the title compound as a white crystalline compound. X H 10 NMR (360MHz, D 2 0) d 1.61-1.74 (IH, m, CHH), 1.76-1.88 (IH, m, CHH), 2.04-2.21 (2H, m, CH 2 ), 3.07-3.23 (IH, m, NCHH), 3.41-3.δl (IH, , NCHH), 3.66 (IH, s, CHO), 4.09 (IH, d, J=13.0Hz, OCHH), 4.2δ (IH, d, J=lδ.δHz, CHH-imidazole), 4.30 (IH, s, CHPh), 4.39 (IH, d, J=lδ.δHz, CHH-imidazole), 4.δδ lδ (IH, d, J=13.0Hz, OCHH), 7.1-7.2 (3H, m, ArH), 7.2-7.3 (2H, m, ArH), 7.38 (2H, s, imidazole-H), 7.48 (2H, s, ArH), 7.51 (IH, s, ArH); MS (CI + ) m z 484 (M++1, 25%). Found: C, 50.32; H, 4.92; N, 7.23; Cl, 12.δ8. Calcd. for C 24 H 23 FeN 3 O.2HCl.H2O: C, δθ.18; H, 4.74; N, 7.32; Cl, 12.34%. 20 EXAMPLE 34 4-rf2S.3SV3-((3.δ-Bisrtrifluoromethyl phenyl methyloxyV 2-phenylpiperidinolmethvHimidazole dihydrochloride This was prepared foUowing the procedure described for 25 Example 33 using the compound of Description 3 and 4-(hydroxymethyl)imidazole as starting materials. This afforded the title compound as a white crystalline compound: mp 206-210°C. *H NMR (360MHz, D 2 0) d 1.73 (IH, m, NCH 2 CH 2 CHH), 1.94-2.06 (IH, m, NCH 2 CH 2 CHH), 2.22-2.40 (2H, m, NCH 2 CH 2 ), 3.33 (IH, mc, NCHH), 3.70-3.81 (IH, m, NCHH), 3.97 (IH, brs, CHO), 4.30 (IH, d, J=12.δHz, OCHH), 4.42(2H, s, NCH 2 -imidazole), 4.δ0 (IH, s, NCHPh), 4.7δ (IH, d, J=12.δHz, OCHH), 7.48 (6H, brs, ArH+imidazole-H), 7.74 (2H, s, ArH), 7.9δ (IH, s, ArH), 8.80 (IH, s, imidazole-H); MS (CI + ) m/z 484 (M + +l Found: C, δθ.22; H, 4.82; N, 7.18; Cl, 12.49. Calcd. for C 24 H 23 F 6 N 3 0.2HC1.H 2 0: C, δθ.18; H, 4.74; N, 7.32; Cl, 12.34% 10 EXAMPLE 35 5-rf(2R*.3R*V3-((3.5-Bi S rtrifluoromethyliphenyl) methvloxv)-2-phenvlpiperidino)methvll-2.3-dihvdro-(4H ' )-3-oxo- 1.2.4-triazole hydrochloride lδ (a) N-Carbomethoxv-2-chloroacetamidrazone Sodium methoxide (0.032g) was added to a solution of chloroacetonitrile (1.26ml) in anhydrous methanol (lδml) at 0°C. The reaction mixture was stirred at room temperature for 20 O.δ hour and then neutralised with acetic add (0.034ml). Methyl hydrazinocarboxylate (1.79g) was added and the reaction mixture stirred at room temperature for O.δ hour. The solution was concentrated in vacuo to give the title compound as an orange sohd. MS (CI) + m/z 166. 25 (b) The compound of Description 1 (0.50g) was stirred with N-carbomethoxy-2-chloroacetamidrazone (0.19g) and potassium carbonate (0.47g) in dimethylformamide (10ml) at 70°C for 18 hours. The reaction mixture was then stirred at M0°C for 1 hour. After cooling, the material was partitioned 30 between ethyl acetate and water. The organic layer was washed with , water, dried (MgS0 4 ), filtered and concentrated. The residue was purified by chromatography on siHca using δ% methanol in ethyl acetate as eluent. The product was recrystaUised from ethyl acetate petrol to give the title compound as a white crystalline sohd. This was characterised as its hydrochloride salt: mp 168-172°C. MS (CI) + m/z δOO ((M+l) + , 18%). Found: C, δ0.6δ; H, 4.43; N, 10.22; Cl, 6.71. Calcd. for C a H M N 4 0 2J5 F β CI: C, 50.60; H, 4.43; N, 10.26; Cl, 6.49%. 10 EXAMPLE 36 5-r(r2R*.3R* -3-r(3.5-Bisftrifluoromethyl phenyl) methyloxyV2-phenvlpiperidinoimethvn-3-(N.N-dimethvlamino)- 1.2.4-thiadiazole lδ (a) 5-(N.N-Dimethvlammo.-1.3.4-oxathiazolin-2-one A solution of cMorocarbonylsulfenyl diloride (ll.δg) in acetonitrile was added to a suspension of N,N-dimethylurea (2δ.0g) in acetonitrile (200ml), over a period of 20 minutes. The reaction mixture was stirred for 1 hour at 23°C, then filtered. 20 Methanol (20ml) was added to the filtrate to decompose excess cMorocarbonylsulfenyl chloride. The solvents were removed in vacuo. The residue was purified by chromatography on siHca using dichloromethane in hexane (3:1) to afford the product as a yeUow ofl. *H NMR (2δOMHz, CDC1 3 ) d 3.04 (6H, s, (CH 3 ) 2 ); MS 2δ (CI + ) m/z l64 (M + +NH 4 + ) (b) 5-(ChloromethylV3-(N.N-dimethylamino thiadiazole Chloroacetonitrile (1.3ml) in dimethylformamide (1ml) was heated to 150-lδδ°C and 5-(N,N-dimethylamino)- l,3,4-oxathiazolin-2-one (l.Og) was added in portions. After δ 30 minutes the reaction mixture was cooled and concentrated in vacuo. The residue was purified by chromatography on siHca using hexane/ethyl acetate (9:1) as eluent. This afforded the product as a wMte crystalline solid. H NMR (2δOMHz, CDC1 3 ) d 3.19 (6H, s, (CH 3 ) 2 ), 4.82 (2H, s, CH 2 ); MS (CI + ) m/z 178 δ (c) 5-r((2R*.3R*V3-((3.5-Bis(trifluoromethvDphenyl) methvloxv)-2-phenvlpiperidinolmethvn-3-fN-N-dimethvlaιmno)- 1.2.4-thiadiazole hydrochloride The compound of Description 1 was reacted with 5-(cMoromethyl)-3-(N,N-dimethylamino)tiιiadiazole according to 10 the procedure described in Example 4. This afforded the title compound as a wMte solid: mp 160-161°C; -Η. NMR (360MHz, DMSO-d 6 + TFA) d 1.69-1.87 (2H, m, CH 2 ), 2.01-2.26 (2H, m, CH 2 ), 3.10 (6H, s, (CH 3 ) 2 ), 3.22-3.34 (IH, m, CHH), 3.64-3.72 (IH, m, CHH), 3.90 (IH, s, CHO), 4.26-4.34 (2H, m, CH 2 ), 4.61 lδ (IH, d, J=20.0Hz, OCHH), 4.76-4.82 (2H, m, OCHH + CHPh), 7.36-7.62 (δH, m, ArH), 7.87 (2H, s, ArH), 7.99 (IH, s, ArH). EXAMPLE 37 5-r{(2S.3SV3-((3.5-Bis(trifluoromethvnphenyl)methyloxy)- 20 2-phenylpiperidinolmethvntetrazole TMs compound was prepared according to the procedure described in Example 7, using the compound of Description 9 as a starting material: mp 179-181°C. MS (CI + ) m/z 486 (MH + , 3δ%). Found: C, δ4.61; H, 4.53; N, 14.37. Calcd. for 25 C, 54.43; H, 4.36; N, 14.43%. EXAMPLE 38 5-rf2S.3SV3-(r3.5-Bis(trifluoromethyl)phenvLmethvloxv)- 2-phenylpiperidino}methyll-2-methyltetrazole TMs compound was prepared according to the procedure described in Example 18 using the compound of Example 37 as a starting material. TMs afforded the title compound as a wMte crystalline material: mp 158-lδ9°C. MS (CI + ) m/z δOO (MH + , 70%). Found: C, δ5.84; H, 4.66, N, 14.13. Calcd. for C, 5δ.31; H, 4.64; N, 14.02%. 10 EXAMPLE 39 δ-rf(2S.3S)-3-((3:5-Bis(trifluoromethyl)phenyl)methyloxyV 2-phenylpiperidinolmethyll-l-methyltetrazole TMs compound was prepared according to the procedure lδ described in Example 19 using the compound of Example 37 as a starting material. TMs afforded the title compound as a dear oU. MS (Cl*) δOO (MH + , 40%). Found: C, δδ.27; H 4.69; N, 13.67. Calcd. for CaaHagF β j O: C, δ5.31; H, 4.64; N, 14.02%. 20 EXAMPLE 40 3-rf(2S.3S)-3-rr3.5-Bis(trifluoromethyl phenyl methyloxy)- 2-phenylpiperidinolmethyripyridazme (a) 3-(HvdroxvmethvL-1.2-pvridazine l,2-pyridazine-3-carboxaldehyde (0.89g) (G. Heimsch, E. 25 Luszczak and M. PaUer, Mh. Chem 104, 1372 (1973)) was dissolved in water and sodium iiorohydride (0.081g) was added carefuUy. After 1 hour no starting material was present by TLC using 10% methanol in dicMoromethane as eluent. The water was removed in vacuo to afford a gum. The gum was extracted with dicMoromethane, the combined organics were dried (MgS0 4 ) and concentrated in vacuo to afford the alcohol as a δ sohd, wMch was used in the following experiment without further purification. Η NMR (360MHz, CDC1 3 ) d δ.04 (2H, s, CH 2 OH), 7.δ4 (IH, dd, pyridazine-H), 7.6δ (IH, dd, pyridazine-H), 9.17 (IH, dd, pyridazine-H). (b) 3-rf(2S.3S 3-((3.5-Bis(trifluoromethyl)phenyl) 0 methyloxy)-2-phenylpiperidino)methyl1pyridazine 3-(Hydroxymethyl)-l,2-pyridazine was dissolved in anhydrous dicMoromethane under an atmosphere of nitrogen and cooled in an ice/water bath. Triethylamine (0.68ml) and methanesulfonyl cMoride (0.378ml) were added and the reaction 5 stirred for 1 hour. No starting material was present by TLC using 5% methanol in dicMoromethane as eluent. The solvent was removed in vacuo to afford a soHd. The compound of Description 3 (0.48g of free base) was dissolved in dimethylformamide (δml) and added to the solid foUowed by 0 potassium carbonate (0.85g). The mixture was heated at 60°C for 12 hours then poured into water (7δml), extracted with ethyl acetate (3x40ml), dried (MgS0 4 ) and concentrated to afford a brown oU. TMs was purified by chromatography on silica gel using a gradient elution of 10-30% ethyl acetate in petrol. δ Further purification was carried out by medium pressure chromatography; elution with δO/δO ethyl acetate/petrol afforded the title compound as a wMte solid: mp 111-113°C. X H NMR d (360MHz, DMSO-d 6 ) 1.43-1.66 (2H, m, NCH 2 CH 2 CH 2 ), 1.77-1.91 (IH, m, NCH 2 CHH), 2.13-2.24 (2H, m, NCHHCHH), 0 2.7δ-2.87 (IH, NCHH), 3.27-3.3δ (IH, d, NCHH-pyridazine), 3.67-3.70 (2H, NCHPh + CHO), 3.83-3.93 (IH, d, NCHH-pyridazine), 4.14 (IH, d, J=13Hz, OCHHAr), 4.66 (IH, d, J=13Hz, OCHHAr), 7.23-7.3δ (3H, m, Ar-H), 7.δ0-7.δ6 (2H, m, ArH), 7.66 (2H, s, pyridazine-H), 7.71 (2H, s, ArH), 7.94 (IH, s, ArH), 9.H (IH, m, 4H) MS (CI + ) m/z 496 ((M++1), 30%) EXAMPLE 41 2-rf(2S.3S)-3-((3.5-Bis(trifluoromethyl)phenyl)methyloxy)- 2-phenylpiperidino)methyll-1.3.δ-triazine 10 The compound of Description 3 (2g), cMoroacetamidine hydrocMoride (1.17g) and dnsopropylethylamine (3.17ml) were dissolved in acetonitrile (10ml) and the resulting mixture was stirred at 60°C, under nitrogen, for 12h. The resulting mixture lδ was evaporated and the residue was dispersed between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate (2xδ0ml) and dicMoromethane (2xδ0ml). The combined organic fractions were washed with brine, dried (MgS0 4 ) and evaporated. The residue was purified by chromatography on 20 siHca using δ% methanol in dicMoromethane and gradient elution to 10% methanol, 1% aqueous ammonia in dicMoromethane. TMs afforded the intermediate amidine as a semi-soHd material, wMch was not further purified. The intermediate amidine (2g) and l,3,δ-triazine (0.3δg) 2δ were dissolved in acetonitrile (7ml) and heated at reflux for 12h. The solution was cooled and evaporated and the residue was purified by chromatography on siHca using δ0% petrol in ethyl acetate as eluent. TMs afforded the product as a crystalline soHd wMch was recrystaUised from hexane: mp 117-119°C. -Η. NMR 30 (360MHz DMSO-d 6 ) δ 1.41-1.60 (2H, m, NCH 2 CH 2 CH 2 ), 1.81- 1.94 (IH, m, NCH 2 CHH), 2.12-2.21 (IH, m, NCH 2 CHH), 2.34- 2.41 (IH, m, NCHH), 2.99-3.06 (IH, m, CHH), 3.26-3.30 (IH, J=lδ.0Hz, NCHH-triazine), 3.61 (IH, bs, CHO), 3.71 (IH, bs, CHPh), 3.80 (IH, d, J=15.0Hz, NCHH-triazine), 4.08 (IH, d, J=13.0Hz, OCHHAr), 4.63 (IH, d, J=13.0Hz, OCHHAr), 7.18- 7.29 (3H, m, ArH), 7.48-7.52 (2H, m, ArH), 7.68 (2H, s, ArH), 7.13 (IH, s, ArH), 9.20 (2H, s, triazine-H). MS (CI+) m/z, 497 (M++1, 100%). EXAMPLE 42 5-ri(2S.3S)-3-((3-f-Butyl-5-methylphenyl)methyloxyV2- (phenvlpiperidino}methvll-2.3-dihvdro-3-oxo-1.2.4-triazole The compound of Description 10 was reacted according to the procedure described in Example 35 to afford the title compound as a crystaUine soHd: mp 18δ-187°C. Η NMR (360MHz, CDC1 3 ) δ 1.22 (10H, m, C(CH 3 ) 3 + NCH 2 CH 2 CHH), 1.38-1.58 (2H, m, NCH 2 CHHCHH), 1.98-2.26 (5H, m, CH 3 + NCHHCHH), 2.89 (IH, d, J=lδ.0Hz, NCHH-triazole), 2.96-3.04 (IH, m, NCHH), 3.29 (IH, bs, CHO), 3.δ6 (IH, bs, CHPh), 3.6δ (IH, J=lδ.0Hz, NCHH-triazole), 4.13 (IH, d, J=12.0Hz, OCHHAr), 4.28 (IH, d, J=12.0Hz, OCHHAr), 6.δ3 (IH, s, ArH). 6.89 (IH, s, ArH), 7.00 (IH, s, ArH), 7.26-7.38 (3H, m, ArH), 7.4δ-7.δ0 (2H, m, ArH). MS (CI + ) m z 43δ (M++1, 60%). Found: C, 72.10; H, 7.94; N, 13.06. Calcd for C 2β u N 4 0 2 : C, 71.86; H, 7.89; N, 12.89%. EXAMPLE 43 2-r((2S.3SV3-((3.5-DicMorophenyl)methyloxy)-2- (phenylpiperidino)methyllimidazole dihvdrochloride The compound of Description 11 was reacted according to the procedure described in Examples 32/33, to afford the title compound: mp 129-131°C. VB NMR (360MHz, DMSO-d 6 ) δ 1.84- 5 1.98 (2H, m, NCH 2 CH 2 CH 2 ), 2.14-2.24 (IH, m, NCH 2 CHH), 2.44-2.62 (IH, m, NCH 2 CHH), 3.09-3.20 (IH, m, NCHH), 3.69- 3.86 (2H, m, NCHH + CHO), 4.25 (IH, d, J=13.0Hz, OCHHAr), 4.53 (IH, d, J:=13.0Hz, OCHHAr), 4.83 (IH, d, J=15.0Hz, NCHH-imidazole), 4.91 (IH, bs, CHPh), 5.14 (IH, d, J=15Hz, 10 NCHH-imidazole), 7.16-7.48 (10H, m, ArH), 7.84 (IH, bs, N-H). MS (CI÷) m/z41δ (M+1+, 70%). Found: C, 60.71; H, 5.28; N, 8.05. C 22 H 23 Cl 2 N 3 O.2HCl.2H 2 O requires; C, 50.30; H, 5.δ6; N, 7.99%. EXAMPLE 44 lδ 5-r{f2S.3SV3-r(3-CMoro-5-methylphenyl ' )methyloxy)-2- phenvlpiperidino)methvπ-2.3-dihvdro-3-oxo-1.2.4-triazolft The compound of Description 12 was reacted according to 20 the procedure described in Example 3δ to afford the title compound as a wMte crystaUine soHd: mp 227-228°C. *H NMR (360MHz, DMSO-dβ) δ 1.35-1.55 (2H, m, NCH 2 CH 2 CH 2 ), L78- 1.88 (IH, m, NCH 2 CHH), 2.06-2.13 (2H, m, NCHHCHH), 2.20 (3H, s, CH 3 ), 2.73 (IH, d, J=14.0Hz, NCHH-triazole), 2.89 (IH, 25 d, J=11.0Hz, NCHH), 3.32-3.39 (IH, m, CHO), 3.42 (IH, d, J=M.0Hz, NCHH-triazole), 3.47 (IH, s, CHPh), 3.86 (IH, d, J=12.0Hz, OCHH), 4.29 (IH, d, J=12.0Hz, OCHH), 6.6δ (IH, s, ArH), 6.79 (IH, s, ArH), 7.07 (IH, s, ArH), 7.25-7.34 (3H, m, ArH), 7.51-7.53 (2H, m, ArH). MS (CI + ) m/z 412 (M++1, 20%). 30 Found: C, 64.30; H, 6.13; N, 13.67. CaaH^Cl A requires: C, 63.99; H, 6.10; N, 13.57%. EXAMPLE 45 5-r((2S.3S)-3-((3.5-Bis(trifluoromethvDphenyl)methyloxy- 2-(diphenylmethyl)pyrrolidinolmethyll-2.3-dihvdro-3-oxo-1.2.4- 5 triable The compound of Description 13 was reacted with N- carbomethoxy-2-cMoroacetamidrazone according to the procedτire described in Example 35 to afford the product as a 0 wMte crystaUine sohd. *H NMR (250MHz, CDC1 3 ) δ 1.92 (2H, m), 2.62 (IH, m), 2.90 (IH, d, J=15Hz), 3.14 (2H, m), 3.78 (2H, m), 4.08 (IH, m), 4.28 (2H, m), 7.1-7.4 (10H, m, ArH), 7.48 (2H, s, ArH), 7.77 (IH, s, ArH). MS (CI + ) m/z 577 (M + +l, 100%). 5 EXAMPLE 46 5-r((2R.3S)-3-((3.5-Bis(trifluoromethyl)phenyl)methyloxy- 2-(diphenylmethyl)pyrrolidino}methvn-2.3-dihvdro-3-oxo-1.2.4- friazpte 0 The compound of Description 14 was reacted with N- carbomethoxy-2-cMoroacetamidrazone according to the procedure described in Example 35 to afford the title compound as a wMte crystaUine soHd. *H NMR (360MHz, CDC1 3 ) δ 2.00 δ (2H, m), 2.69 (IH, m), 3.03 (IH, t, J=7.5Hz), 3.26 (IH, d, J=14.5Hz), 3.32 (IH, d, J-=M.5Hz), 3.68 (2H, s), 3.76 (IH, d, J=3.5Hz), 4.31 (IH, d, J=12.5Hz), 4.42 (IH, d, J=12.δHz), 7.40- 7.19 (10H, m, ArH), 7.64 (2H, s, ArH), 7.76 (IH, s, ArH). MS (CI+) m/z 577 (M++1, 100%). 0 EXAMPLE 47 3-r(2S.3S)-3-(r3.5-DicMorophenyl)methyloxy)-2- (diphenylmethyl)pyrrolidino}methyll-1.2.4-triazole The compound of Description lδ was reacted with N- formyl-2-cMoroacetamidrazone according to the procedure in Example 16 to afford the title compound as a crystaUine soHd: mp 128-129°C. -B NMR (360MHz, DMSO-dβ) δ 1.6δ (IH, brs), 1.76 (IH, brs), 3.10 (2H, m), 3.61 (IH, d, J=12.0Hz), 3.92 (IH, brs), 4.01 (IH, brs), 4.22 (2H, m), 7.02 (2H, d, J=1.8Hz, ArH), 7.10 (IH, m, ArH), 7.14 (3H, m, ArH), 7.22 (2H, t, ArH), 7.39 (2H, d, ArH), 7.46 (3H, m, ArH). MS (CI + ) m/z 493 (M++1, 60%). Found: C, 65.96; H, 5.22; N, 11.33. Calcd for C 27 H 26 C1 2 N 4 0: C, 65.72; H, 5.31; N, 11.36%. EXAMPLE 48 5-r{(2S.3S)-3-((3- -Butyl-5-chlorophenyl)methyloxyV2- phenvlpiperidino)methvll-2.3-dihvdro-3-oxo-1.2.4-triazole The compound of Description 16 was reacted with N- carbomethoxy-2-c-Moroacetamidrazone, according to the procedure described in Example 35, to afford the title compound as a wMte crystaUine sohd: mp 181-182°C. MS (CI + ) m/z 4δδ (M++1, 100%). Found: C, 65.99; H, 6.87; N, 12.31. Calcd for C 25 H 31 C1N 4 0: C, 66.47; H, 6.91; N, 12.45%. EXAMPLE 49 δ-r((2S.3S)-3-((3-Bis(trifluoromethvDphenyl)methyloxy-2- phenvlpiperidinolmethyl1-2.3-dihvdro-3-oxo-1.2.4-triazole 5 hydrochloride The titie compound was prepared according to the procedure described in Example 3δ, using the compound of Description 3 as starting material. The hydrocMoride salt was 10 recrystaUised from ethyl acetate-methanol to give a wMte crystaUine soHd: mp 26δ-266°C. -B NMR (360MHz, DMSO-d 6 + TFA) δ 1.76-1.95 (2H, m, CH 2 ), 2.04-2.30 (2H, m, CH 2 ), 3.20-3.32 (IH, m, NCHH), 3.58-3.69 (IH, m, NCHH), 3.90 (IH, d, J=15.0Hz, NCHH-triazole), 3.93 (IH, s, CHO), 3.94 (IH, d, lδ J=lδ.0Hz, NCHH-triazole), 4.30 (IH, d, J=12.0Hz, OCHH), 4.73 (IH, bs, CHPh), 4.80 (IH, d, J=12.0Hz, OCHH), 7.42 (3H, brs, ArH), 7.56 (2H, brs, ArH), 7.89 (2H, s, ArH), 7.95 (IH, s, ArH). MS (CI+) m/z δOl (M++1), 60%). Found: C, 51.41; H, 4.15; N, 10.58; Cl, 6.46. Calcd for CgaHgaFe HCl: C, 51.46; H, 4.32; N, 20 10.44; Cl, 6.60%. EXAMPLE 50 3-r{(2S.3S -3-((3.5-Bis(trifluoromethyl)phenyl)methyloxy)- 25 2-phenvlpiperidinolmethvn-l-methvl-1.2.4-triazole hydrpchlprjde The compound of Example 30 (O.δg) was dissolved in methanol in a tube. Sodium (0.03g) and iodomethane (0.075ml) 0 were added and the container was sealed. The resulting solution was heated at 65°C for lh, cooled and evaporated. The residue was suspended between water and ethyl acetate. The organic layer was dried (MgS0 4 ), filtered and the solvent removed in vacuo. The residue was purified by chromatography on siHca using ethyl acetate as eluent. TMs afforded the product as a 5 colourless oU, wMch was converted to the hydrocMoride salt by addition of ethereal hydrogen cMoride. The salt was recrystaUised from ether/petrol. X H NMR (360MHz, DMSO-dg) δ 1.70-1.84 (2H, m, CH 2 ), 2.12-2.51 (2H, m, CH 2 ), 3.36 (3H, s, NCH 3 ), 3.52 (IH, brs, CHHN), 3.73 (IH, brs, CHHN), 3.87 (IH, 10 s, CHO), 4.25 (2H, m, CHH-triazole), 4.28 (IH, d, OCHHAr), 4.65 (IH, brs, NCHPh), 4.78 (IH, d, OCHHAr), 7.41 (3H, s, ArH), 7.60 (2H, brs, ArH), 7.93 (2H, s, ArH), 7.96 (IH, s, ArH), 8.05 (IH, s, CH=NH (triazole)); MS (CI+) m/z 499 (M++1, 85%). lδ EXAMPLE 51 3-r{(2S.3S -3-(r3.5-Bi S (trifluoromethvDphenvLmethvloxvV 2-phenylpiperidino)methvn-δ-phenvl-1.2.4-oxadiazole hydrochloride 20 The compound of Description 3 was reacted with 3- cMoromethyl-5-phenyl-l,2,4-oxadiazole according to the procedure described in Example 26. The product was characterised as its hydrocMoride salt: mp 88-90°C. -B NMR 2δ (360MHz, CDClg, free base) δ 1.50-1.64 (2H, m, CH 2 ), 2.06-2.22 (2H, m, CH 2 ), 2.44-2.56 (IH, m, CHHN), 3.18-3.28 (IH, m, CHHN), 3.60 (IH, s, CHO), 3.66-3.74 (IH, d, J=lδ.0Hz, NCHH- oxadiazole), 3.78 (IH, s, CHPh), 3.88-3.98 (IH, d, J=15.0Hz, NCHH-oxadiazole), 4.02-4.10 (IH, d, J---.12.0Hz, OCHHAr), 4.44- 30 4.δ2 (IH, d, J=12.0Hz, OCHHAr), 7.28-7.64 (10H, m, ArH), 7.68 (IH, s, ArH), 8.08-8.18 (2H, m, ArH); MS (CI + ) m z 562 (M++1). EXAMPLE 62 3-r((2R*.3R*V3-((3.5-Bis(trifluoromethyl)phenyl) methvloxv)-2-phenvlpiperidino)methvll-5-tMomethvl-1.2.4- triazole hydrochloride Sodium methoxide (.OOlg) was added to a solution of the compound of Example 17 (.10g) in ethanol (5ml) and the mixture was heated at reflux for 10 min. Methyl iodide (0.012ml) in ethanol (1ml) was added and the mixture was heated at reflux for 3h. The solvent was then removed in vacuo and the residue was partitioned between ethyl acetate and water. The orgamc layer was dried (MgS0 4 ) and concentrated in vacuo. The residue was purified by chromatography on siHca using 50% ethyl acetate in petrol as eluent. The compound was isolated as the hydrocMoride salt by treatment of the free base with methanolic hydrogen cMoride: mp 10δ-107°C. *H NMR (360MHz, DMSO-d 6 + TFA) δ 1.73-1.91 (2H, m, CH 2 ), 2.05-2.20 (IH, m, CHH), 2.21-2.30 (IH, m, CHH), 2.63 (3H, s, CH 3 ), 3.28 (IH, m, NCHHCH 2 ), 3.73 (IH, m, NCHHCH 2 ), 3.92 (IH, brs, CHO), 4.10 (2H, dd, J=20Hz, 14.5Hz, NCH 2 ), 4.29 (IH, d, J=13Hz, OCHH), 4.68 (IH, s, CHPh), 4.79 (IH, d, J=13Hz, OCHH), 7.42-7.48 (3H, m, ArH), 7.57 (2H, brs, ArH), 7.88 (2H, s, ArH), 7.95 (IH, s, ArH). MS (CI + ) m/z 531 (M++1, 44%). Found: C, 51.29; H, 4.62; N, 9.79; Cl, 6.06. Calcd for C 29 H 24 F 6 N 4 OS.HCl: C, 50.84; H, 4.44; N, 9.88; Cl, 6.25%. EXAMPLE 53 5-rff2S.3S)-3-((3.5-DicMorophenyl)methyloxy.-2- phenylpiperidino)methvn-2.3-dihvdro-3-oxo-1.2.4-triazole The compound of Description 11 was reacted according to the procedure described in Example 35 to afford the title compound wMch was recrystaUised from hot dimethylformamide: mp >220°C. Η NMR (360MHz, DMSO-d 6 , 353K) δ 1.45-1.58 (2H, m, CH 2 ), 1.81-1.95 (IH, m, CHH), 2.02- 2.12 (IH, m, CHH), 2.18 (IH, dt, J=2.5, 11.5Hz, NCHHCH 2 ), 2.82 (IH, d, J=M.2Hz, NCHH), 2.94 (IH, brd, NCHHCH 2 ), 3.40 (IH, d, J=M.5Hz, NCHH), 3.45 (IH, d, CHO), 3.52 (IH, d, CHPh), 3.91 (IH, d, J=12.5Hz, OCHH), 4.34 (IH, d, J=12.5Hz, OCHH), 7.21-7.37 (5H, m, ArH), 7.47-7.55 (3H, m, ArH). EXAMPLE 54 4-rf(2R*.3R*V3-((3-CarbomethoxyphenylιmethyloxyV2- phenvlpiperidinolmethvlTpvridinium dichloride The compound of Description 17 was reacted with 4- picolyl cMoride according to the procedure described in Example 4 to afford the title compound. -Η. NMR (250MHz, CDC1 3 ) δ 1.42- 1.61 (2H, m, NCH 2 CH 2 CH 2 ), 1.98-2.18 (3H, , NCHHCH 2 ), 2.87-3.04 (2H, m, NCHH-pyridine + NCHH), 3.31-3.39 (IH, m, CHO), 3.48-3.54 (IH, m, NCHPh), 3.86 (IH, d, J=MHz, NCHH- pyridine), 3.93 (3H, s, OCH 3 ), 4.06 (IH, d, J=llHz, OCHHAr), 4.30 (IH, d, J=llHz, OCHHAr), 7.12 (IH, m, ArH), 7.22-7.39 (6H, m, ArH), 7.45-7.56 (2H, dd, pyridine-H), 7.77 (IH, bs, ArH), 7.85-7.92 (IH, ArH), 8.46-8.55 (2H, dd, pyridine-H). MS (CI+) m/z 417 (M++1, 50%). Found: C, 64.10; H, 6.06; N, 5.62. 0 26 ^^0 3 2^1 requires: C, 63.80; H, 6.18; N, 5.72%. - 9δ EXAMPLE 55 4-rf(2R*.3R* 3-(f3-Carboxamidophenyl.methyloxy)-2- phenvlpiperidinolmethvnpvridine The compound of Description 18 was reacted with 4- picolyl cMoride according to the procedure described in Example 4 to afford the title compound. -B NMR (360MHz, CDC1 3 ) 1.43- 1.56 (2H, m, NCH 2 CH 2 CH 2 ), 2.00-2.17 (3H, m, NCHHCH 2 ), 2.88-3.04 (2H, m, NCHH + NCHHAr), 3.35 (IH, m, CHO), 3.54 (IH, bs, CHPh), 3.83 (IH, d, J=14.5Hz, NCHHAr), 4.08 (IH, d, J=12Hz, OCHHAr), 4.35 (IH, d, J^Hz, OCHHAr), 5.6-6.16 (2H, bs, CONH 2 ), 7.11-7.74 (11H, m, ArH), 8.48 (2H, d, J=4Hz, pyridine-H). MS (CI + ) m/z 402 (M++1, 20%). EXAMPLE 56 5-r((2R*.3R*)-3-((2-Methoxv-3-nitrophenvl)methvloxvV2- phenylpiperidino}methyll-3-methyl-1.2.4-oxadiazole The compound of Description 19 was reacted according to the procedure described in Example 2 to afford the title compound. *H NMR (360MHz, CDC1 3 ) δ 1.48-1.64 (2H, m, NCH 2 CH 2 CH 2 ), 2.09-2.25 (2H, m, NCH 2 CH 2 ), 2.37 (3H, s, CHg), 2.41-2.51 (IH, m, NCHH), 3.12-3.20 (IH, m, NCHH), 3.59 (IH, bs, CHO), 3.64 (IH, bs, CHPh), 3.73 (IH, d, J=16Hz, NCHH- het), 3.80 (3H, s, OCHa), 3.91 (IH, d, J=16Hz, NCHH-het), 3.98 (IH, d, J=13Hz, OCHHAr), 4.48 (IH, d, J=13Hz, OCHHAr), 6.78 (IH, d, J=9Hz, H), 7.22-7.37 (3H, m, ArH), 7.48-7.54 (2H, bd, ArH), 8.09-8.14 (IH, dd, J=9Hz, J=3Hz, ArH), 8.15-8.18 (IH, d, J=3Hz, ArH). MS (CI + ) m/z 439 (M++1, 100%). EXAMPLE 57 3-Amino-5-rf(2R*.3R*)-3-f(5-amino-2-methoxyphenvD methyloxy)-2-phenylpiperidino)methvn-1.2.4-oxadiazole The compound of Description 20 was reacted according to the procedure described in Example 1 to afford the title compound. H NMR (360MHz, CDC1 3 ) δ 1.41-1.60 (2H, m, NCH 2 CH 2 CH 2 ), 2.13-2.24 (2H, m, NCH 2 CΗ 2 ), 2.31 (IH, m, NCHH), 3.12-3.21 (IH, m, NCHH), 3.39 (IH, d, J=16Hz, NCHH- het), 3.47 (IH, m, CHO), 3.56 (IH, m, NCHPh), 3.61 (3H, s, OCHa), 3.82 (IH, d, J=16Hz, NCHH-Het), 4.13 (IH, d, J=13Hz, OCHHAr), 4.34 (IH, d, J=13Hz, OCHHAr), 5.17 (2H, bs, NH 2 ), 6.38 (IH, bs, ArH), 6.43-6.48 (IH, m, ArH), 6.54-6.68 (IH, d, J=8.5Hz, ArH), 7.26-7.58 (3H, m, ArH), 7.48-7.54 (2H, m, ArH). EXAMPLE 58 6-rfr2S.3S)-3-((3.5-Bis(trifluoromethyl phenyl methyloxyV 2-phenylpiperidinolmethvnuradl The compound of Description 3 was reacted with 6- (cMoromethyl)uradl foUowing the conditions described in Example 4 to afford the title compound. -E. NMR (360MHz, CDC1 3 ) 1.52-1.71 (2H, m, NCH 2 CH 2 CH 2 ), 1.99-2.25 (3H, m, NCHHCH 2 ), 2.69 (IH, d, J=16Hz, NCHH-uradl), 2.92-3.01 (IH, m, NCHH), 3.38-3.40 (IH, m, CHO), 3.52-3.62 (2H, m, NCHH- uradl + NCHPh), 4.08 (IH, d, J=12Hz, OCHHAr), 4.49 (IH, d, J=12Hz, OCHHAr), 5.41 (IH, s, H A ), 7.32-7.40 (5H, m, ArH), 7.60 (2H, s, H), 7.δ6 (IH, s, H), 8.64-9.04 (2H, bs, NH + NH). MS (CI + ) m/z 528 (M+l + , 100%). requires C, 56.93; H, 4.40; N, 7.97%. Found C, 57.16; H, 4.03; N, 7.88%. EXAMPLE 59 3-r((2R*.3R*V3-(f3.5-Bis(trifluoromethvl phenvl) methvloxv)-2-phenylpiperidino)methvl1-5-carboxamido-1.2.4- triazole The compound of Description 1 was reacted with 2-cMoro- N-carboxamidoacetamidhydrazone according to the procedure described in Example 35 to afford the title compound as a wMte sohd: mp 195°C. υ^ (KBr) 1680cm- i ; Found: C, 55.14; H, 4.58; N, 12.82. Calcd for C, 54.65; H, 4.40; N, 13.27%. EXAMPLE 60 3-r{(2R*-3R*V3-ff3.S-Bis(trifluoromethvl;phenvl) methvloxv)-2-phenvlpiperidino)methvl1-5-cvano-1.2.4-triazole The compound of Example 59 (0.61g) was dissolved in cMoroform (10ml) and the resulting solution was cooled to 0°C in an ice bath. Triethylamine (2ml) was added followed by phosphorus oxycMoride (1.2ml), dropwise. The solution was stirred at room temperature for lh. The solvent was removed in vacuo and the residue was dispersed between cMoroform and sodium hydrogen carbonate. The organic layer was washed with brine, dried (MgS0 4 ), filtered and concentrated in vacuo. The residue was purified by column chromatography on silica using 30% petrol in ethyl acetate as eluent. The product was isolated as the hydrocMoride salt using ethereal hydrogen cMoride: mp 81°C. MS (CI + ) m/z 510 (M++1, 60%). EXAMPLE 61 -rπ S l -((2S-3SV3-f(3.5-Dichlorophenyl methyloxy)-2- phenvlpiperidino)ethvl1-1.2-4-triazole (a) (±) N-Formyl-2-chloropropionamidohvdrazone Sodium methoxide (.162g) was added to a solution of 2- cMoropropiomtrile (lO.δg) in anhydrous methanol (150ml) at 0° C. The reaction mixture was stirred at room temperature for lh, then neutraHsed with acetic add (.18ml). N-Foπnylhydrazine (7.04g) was added and the mixture was stirred overnight. The resulting pink solution was concentrated in vacuo to give the title compound as a pink soHd. (b) The compound of Description 11 (δ.9g) was dissolved in dimethylformamide ,(46ml) and N-formyl-2- cMoropropionamidohydrazone (3.5g) was added, foUowed by potassium carbonate (δ.7g). The mixture was stirred at room temperature for 2h, then diluted with xylene (150ml) and heated at reflux for 2h. When cool, the mixture was filtered and concentrated in vacuo to afford a brown residue. Crude *H NMR indicated a mixture of diastereoisomers in 3:1 ratio. The residue was purified by medium pressure chromatography (Lobar) on siHca using 4% methanol in dicMoromethane as eluent. The first product eluted, diastereoisomer 1, was isolated as a foam wMch was recrystaUised from ether-hexane: mp 10δ-107°C Η NMR (360MHz, CDC1 3 ) δ 1.31 (3H, d, J=7.0Hz, -CHCHg), 1.52-1.69 (2H, m, NCH 2 CHHCHH), 2.02-2.05 (IH, m, NCH 2 CHH), 2.05- 2.16 (IH, m, NCH 2 CH 2 CHH), 2.51 (IH, t, J=11.5Hz, NCHH), 2.62 (IH, m, NCHH), 3.56 (IH, s, CHO), 3.77 (IH, s, CHPh), 3.99 (IH, d, J=12.0Hz, OCHH), 4.22 (IH, q, J=7.0Hz, -CHCH 3 ), 4.30 (IH, d, J=12.0Hz, OCHH), 6.89 (2H, d, J=2.0Hz, ArH), 7.21 (IH, t, J=2.0Hz, ArH), 7.3-7.4 (3H, m, ArH), 7.40-7.47 (2H, m, ArH), 7.89 (IH, s, triazole-2H). MS (CI + ) m/z. EXAMPLE 62 3-r(lRVl-{(2S.3SV3-((3.5.DicMorophenyl methyloxy)-2- phenylpiperidinolethyll- 1.2 ,4-triazole The second product isolated from the column described in Example 61 was recrystaUised from ether to afford the title compoτmd whose stereochemistry was established from Η NMR n.0.e. experiments: mp 132-134°C Η NMR (360MHz, DMSO-d f ,) δ 1.06-1.15 (IH, m, NCH 2 CH 2 CHH), 1.35 (3H, d, J=7.0Hz, CHCHa), 1.34-1.42 (IH, m, NCH 2 CHH), 1.66-1.85 (2H, m, NCHHCHH), 1.98-2.02 (IH, m, NCH 2 CH 2 CHH), 3.01-3.03 (IH, d, J=10.5Hz, NCHH), 3.39 (IH, s, CHO), 3.86 (IH, d, J=13.0Hz, OCHH), 3.98 (IH, q, J=7Hz, CΗCH 3 ), 4.33 (IH, d, J=13.0Hz, OCHH), 6.92 (IH, d, J=2.0Hz, ArH), 7.26-7.46 (6H, m, ArH, EXAMPLE 63 3-r((2S.3SV3-((2.3-Dimethylphenyl)methyloxy)-2- phenylpiperidino)methyl1-1.2.4-triazole FoUowing the method described in Example 16, the compound of Description 23 (lOOmg) was reacted with 69mg of N-foπnyl-2-cMoroacetamidohydrazone, to give the title compound. Η NMR (CDC1 3 ) δ 1.50 (2H, m), 1.94 (3H, s), 2.0- 2.35 (3H, m), 2.2 (3H, s), 3.02 (IH; m), 3.45 (2H, m), 3.57 (IH, s), 3.95 (IH, br s), 3.95 (IH, d, J=llHz), 4.26 (IH, d, J=llHz), 6.86 (IH, d, J=7Hz), 7.06 (IH, d, J=7Hz), 7.2-7.5 (6H, m), 7.7 (IH, br s). The foUowing compounds were prepared by the procedure described in Example 35. EXAMPLE 64 0 5-rf(2S.3S)-3-((2.3-Dimethylphenyl methyloxy)-2- phenylpiperidino)methyl1-2.3-dihvdro-(4H)-3-oxo-1.2.4-triazole The compound of Description 23 was used as starting 5 material. *H NMR (CDC1 3 ) δ 1.4-1.55 (2H, m), 1.89 (3H, s), 1.9- 2.2 (3H, m), 2.15 (3H, s), 2.91 (IH, d, J=15Hz), 2.9δ (IH, m), 3.28 (IH, s), 3.50 (IH, s), 3.66 (IH, d, J=15Hz), 4.06 (IH, d, J=12Hz), 4.29 (IH, d, J=12Hz), 6.77 (IH, d, J=7Hz), 6.9 (IH, t, J=7Hz), 6.97 (IH, d, J=7Hz), 7.2-7.4δ (5H, m). 0 EXAMPLE 65 5-rf(2S.3SV2-Phenyl-3-r(3-(trifluoromethyl)phenyl) methvloxv)piperidino)methvIl-3-oxo-1.2.4-triazole δ The compound of Description 21 was used as starting material. Η NMR (CDC1 3 ) δ 1.5 (2H, m), 1.9-2.2 (3H, m), 2.91 (IH, d, J=15Hz), 3.0 (IH, m), 3.3 (IH, s), 3.5 (IH, s), 3.64 (IH, d, J=15Hz), 4.12 (IH, d, J=12Hz), 4.41 (IH, d, J=12Hz), 7.0-7.45 0 (9H, m), 9.9 (2H, br s). EXAMPLE 66 5-r((2S.3S)-3-((3.4-DicMorophenyl)methyloxy)-2- phenylpiperidino}methvn-3-oxo-1.2.4-triazole The compom d of Description 22 was used as starting material. Η NMR (CDC1 3 ) δ 1.5 (2H, m), 1.85-2.2 (3H, m), 2.88 (IH, d, J=15Hz), 3.0 (IH, m), 3.27 (IH, s), 3.48 (IH, s), 3.67 (IH, d, J=15Hz), 4.05 (IH, d, J=12Hz), 4.35 (IH, d, J=12Hz), 6.7 (IH, br d, J=7Hz), 6.95 (IH, br s), 7.16 (IH, d, J=7Hz), 7.2-7.45 (5H, m), 9.8 (IH, br s), 10.5 (IH, br s). EXAMPLE 67 5-rf(2S.3S -3-(f3-<-Butvlphenvl)methvloxv)-2- phenylpiperidino}methvH-3-oxo-1.2.4-triazole The compound of Description 24 was used as starting material. Η NMR (CDC1 3 ) δ 1.23 (9H, s, C(CH 3 ) 3 ), 1.40-1.51 (2H, m, CH 2 ), 1.82-1.85 (IH, m, CHH), 2.01-2.14 (2H, m, CHH and NCHH), 2.74 (IH, d, J=14Hz, NCIffi-triazolone), 2.88 (IH, m, NCHH), 3.38 (IH, d, J=MHz, NCHH-triazolone), 3.40 (IH, m, NCHCHO), 3.51 (IH, s, NCHCHO), 3.85 (IH, d, J=12Hz, OCHH), 4.23 (IH, d, J=12Hz, OCHH), 6.80-6.82 (IH, m, ArH), 7.06-7.34 (6H, m, ArH), 7.53-7.65 (2H, m, ArH), 11.16 (IH, s, NH), 11.24 (IH, s, NH); MS (CI+) m/z 420 (M++1, 10%). Found: C, 71.51; H/7.51; N, 13.08. Cadd. for C 25 H 32 N 4 0: C, 71.40; H, 7.67; N, 13.32%. EXAMPLE 68 5-rf(2R*-3R*V3-r(3.5-Dimethvlphβnvl)methvloxv)-2- phenvlpiperidino}methvn-3-oxo-1.2.4-triazole The compound of Description 25 was used as starting material. *H NMR (360MHz, DMSO-dβ) δ 1.41-1.47 (2H, m, CH 2 ), 1.81-1.85 (IH, m, CHH), 2.05-2.11 (2H, m, CHH and NCHH), 2.15 (6H, s, CH 3 ), 2.72 (IH, d, J=14Hz, NCHH- triazolone), 2.86-2.89 (IH, m, NCHH), 3.36 (IH, d, J=2.5Hz, CHO), 3.40 (IH, d, J=MHz, NCHH-triazolone), 3.44 (IH, brs, CHPh), 3.82 (IH, d, J=12Hz, OCHH), 4.20 (IH, d, J=12Hz, OCHH), 6.50 (2H, s, ArH), 6.79 (IH, s, ArH), 7.25-7.33 (3H, m, ArH), 7.51-7.63 (2H, m, ArH), 11.16 (IH, s, NH), 11.25 (IH, s, NH). EXAMPLE 69 (2S.3S -3-r(3.5-Bisftrifluoromethyl)phenyl)methyloxy)-2- phenvl-l-(3-(1.2.4-triazoIvl)>piperidine 1-Hydroxybenzotriazole hydrate (308mg), l-(3- diιnethylaminopiOpyl)-3-ethylcarbodimide hydrocMoride (436mg), triethylamine (0.3ml) and l,2,4-triazole-3-carboxyHc add (129mg) were dissolved in dimethylformamide (5ml) and the resulting mixture was stirred for 15 min. The compound of Description 3 (0.5g) was added and the resulting mixture was stirred at room temperature for 12h. The reaction mixture was diluted with water (100ml) and the product was extracted into ethyl acetate (3 x 50ml). The orgamc fractions were washed successively with ritric add (aqueous), water, potassium carbonate and brine, then dried (MgS0 4 ) filtered and concentrated. The residue was purified by column chromatography on sUica using 70% ethyl acetate in hexane as eluant. The product was recrystaUised from ethyl acetate/petrol to afford a crystaUine wMte solid: mp 77-79°C. MS (CL) m/z 478 ((M-HFh 100%). EXAMPLE 70 (2S.3SV3-((3-5-Bis(triflιmmmethv1 phenvDmethyloxy-l- ( l-oxo-2-pyrid-4-yl)ethyl-2-phenylpiperidinium hydrocMoride The compound of Description 3 was reacted with 4- pyridylacetie add following the procedure outlined in Example 69. TMs afforded a colourless oil wMch was treated with ethereal hydrogen cMoride and the soHd obtained was recrystaUised from benzene hexane. MS (CI + ) m/z 523 (M++1, 100%). Found: C, 54.67; H, 4.86; N, 4.66; Cl, 6.16. Calcd. for C-^F β N ^O: C, 54.50; H, 4.91; N, 4.70; Cl, 5.96%. EXAMPLE 71 (2S.3S -3-((3.5-Bis(trifluoromethyl)phenyl)methyloxy-l- (2-oxo-2-pyrid-3-yl)ethyl-2-phenylpiperidine 3-(Bromoacetyl)pyridinium hydrobromide (336mg) was dissolved in dimethylformamide (3ml) and to tiiis solution was added the compound of Description 3 (440mg) followed by potassium carbonate (550mg). The mixture was stirred at room temperature for 2h, diluted with water and extracted into ethyl acetate. The organic phase was washed with brine, dried (MgS0 4 ) and evaporated. The residue was purified by chromatography on siHca using 70% ether in hexane as eluant and further purified by medium pressure chromatography (Lobar) using ethyl acetate in hexane (60:40) as eluant. -B NMR (250MHz, DMSO-d 6 ) δ 1.4-1.6 (2H, m), 1.8-1.98 (IH, m, CHH), 2.06-2.2 (IH, m, CHH), 2.5-2.6 (IH, m), 2.9-3.0 (IH, ), 3.54 (IH, d, NCHHCO), 3.62 (IH, brs, CHO), 3.74 (IH, d, CHPh), 3.84 (IH, d, OCHH), 7.2-7.3 (2H, m, ArH), 7.38-7.5 (3H, m, ArH), 7.5 (IH, dd, pyr-H), 7.85 (2H, s, ArH), 7.92 (IH, s, ArH), 8.14 (IH, dt, pyr-H), 8.62 (IH, dd, pyr-H), 8.94 (IH, d, pyr-H). EXAMPLE 72 a-ra SV1 -(f2S-3S)-3-r(3.5-Bi S rtrifluoromethylphenyl) methyloxy)-2-phenylpiperidino)ethyll-1.2.4-triazole TMs was prepared from the compound of Description 3 and N-formyl-2-cMoropropionamidohydrazone foUowing the procedure described in Example 61. The first compound to be eluted from the column (using 3% methanol in dicMoromethane as eluant on siHca) was isolated and characterised as the title compound: mp 66-68°C. MS (CI + ) m/z 499 ((M+l) + , 100%). EXAMPLE 73 3-rriRVl-(r2S.3S)-3-fr3.5-BisftrifluoromethvDphenvD methyloxyV2-phenylpiperidino)ethyll-1.2.4-triazole The second product isolated from the column described in Example 72 was recrystaUised from ethyl acetate/hexane to afford the title compound: mp 108-111°C. MS (CI + ) m/z 499 ((M+D+, 100%). EXAMPLE 74 5-r(lS)-1-(f2S.3S)-3-((3.5-Bis(trifluoromethylphenyl) methyloxy)-2-phenylpiperidino)ethyll-2.3-dihvdro-3-oxo-1.2.4- triazole TMs compound was prepared according to the procedure described in Example 35 using the compound of Description 3 and N-carbomethoxy-2-cMoropropionamidohydrazone (C1CH(CH 3 )C(=NH)NHNHC00CH 3 ) as starting materials. Η NMR (CDC1 3 ) δ 0.94 (3H, d, J=7Hz), 1.4-1.58 (2H, m), 1.8 (IH, mc), 2.06-2.2 (IH, m), 2.26-2.4 (IH, m), 3.3 (IH, mc), 3.52 (IH, s), 3.64-3.72 (2H, m), 4.06 (IH, d, J=12Hz), 4.64 (IH, d, J=12Hz), 7.2-7.38 (3H, m), 7.6-7.7 (2H, m), 7.74 (2H, s), 7.94 (IH, s). MS (CI + ) m/z 515 ((M+D + , 23%). EXAMPLE 75 3-rf(2S.3S 3-((3.5-Dichlorophenyl.methyloxy.-2- phenylpiperidino)methvn-1.2.4-triazole TMs was prepared from the compound of Description 11 according to the procedure described in Example 16 to afford the title compound: mp 208-212°C. MS (CI + ) m/z 417 ((M+l) + , 100%). EXAMPLE 76 5-r((2R*.3R*V3-rr3.5-Bisrtrifluoromethyl)phenyl)methyloxy - 2-(3-cMorophenvDpiρeridino)methvn-2.3-dihvdro-(4H)-3-oxo- 1.2.4-triazole TMs was prepared from the compound of Description 26 according to the procedure described in Example 35: mp 125- 127°C. NMR (360MHz, DMSO) δ 1.46-1.52 (2H, m), 1.9-1.95 (IH, m), 2.0-2.2 (2H, m) 2.92 (IH, d, J=15Hz, NCHHtriazolone), 2.98 (IH, mc), 3.3δ (IH, s, CHO), 3.44 (IH, d, J=lδHz, NCHHtriazolone), 3.60 (IH, brs, CHPh), 3.96 (IH, d, J=12Hz, OCHH), 4.43 (IH, d, J=12Hz, OCHH), 7.15-7.22 (2H, m, ArH), 7.37-7.41 (2H, m, ArH), 7.48 (2H, s, ArH), 7.65 (IH, s, ArH). MS (CI + ) m/z 536, 537 (M++1, 100, 30%). EXAMPLE 77 5-r{f2S.3SV3-((3.4-Dimethylphenyl)methyloxyV2- phenylpiperidino}methyl1-2.3-dihvdro-(4HV3-oxo-1.2.4-triazole TMs compound was prepared according to the procedure described in Example 35 using the compound of Description 29 as starting material. *H NMR (CDC1 3 ) δ 1.37-1.55 (2H, m), 1.9- 2.2 (3H, m), 2.1 (3H, s), 2.15 (3H, s), 2.85 (IH, d, J=15Hz), 2.97 (IH, m), 3.26 (IH, s), 3.51 (IH, s), 3.65 (IH, d, J=15Hz), 4.06 (IH, d, J=llHz), 4.26 (IH, d, J=llHz),6.65 (2H, m), 6.9 (IH, d, J=8Hz), 7.2-7.45 (5H, m), 9.5 (IH, brs). EXAMPLE 78 5-rf(2S.3SV3-((3-iPropoxyphenyl methyloxy)-2- phenylpiperidino}methyl1-2.3-dihvdro-(4H)-3-oxo-1.2.4-triazole TMs compound was prepared according to the procedure described in Example 35 using the compound of Description 30 as starting material. *H NMR (CDC1 3 ) δ 1.25 (6H, d, J=6Hz), 1.35-1.55 (2H, m), 1.9-2.2 (3H, m), 2.89 (IH, d, J=15Hz), 2.99 δ (IH, d, J=10Hz), 3.27 (IH, s), 3.δl (IH, s), 3.66 (IH, d, J=15Hz), 4.1 (IH, d, J=12Hz), 4.38 (IH, m), 6.48 (IH, d, J=7Hz), 6.δ7 (IH, s), 6.66 (IH, d, J=7Hz), 7.2-7.6 (5H, m). EXAMPLE 79 5-r((2S.3SV3-((3- uoro-5-methylphenyl.methyloxy)-2- 0 phenylpiperidino}methyll-2.3-dihvdro-(4H)-3-oxo-1.2.4-triazole TMs was prepared by the reaction of the compound of Description 27 according to the procedure outlined in Example 35: mp 228-229°C. Η NMR (360MHz, DMSO) δ 1.4-1.55 (2H, m, CH 2 ), 1.8-1.9 (IH, m, CH 2 ), 2.02-2.18 (2H, m, CH 2 and NCHH), 5 2.21 (3H, s, CH 3 ), 2.73 (IH, d, NCHH-het, J=MHz), 2.87-2.90 (IH, d, NCHH, J=llHz), 3.32-3.40 (IH, m, NCHCHO), 3.41 (IH, d, NCHH-het, J=MHz), 3.46 (IH, s, NCHCHO), 3.87 (IH, d, OCHH-Ar, J=12.5Hz), 4.28 (IH, d, OCHH-Ar, J=12.5Hz), 6.50- 6.5δ (2H, m, ArH), 6.80-6.83 (IH, m, ArH), 7.29-7.31 (3H, m, 0 ArH), 7.51-7.63 (2H, m, ArH), 11.18 (IH, s, NH), 11.28 (IH, s, NH). MS (CI+) m/z 397 (M++1, 10%). EXAMPLE 80 5-r{3-(3R*)-((3.5-Bis(trifluoromethyl phenyl)methyloxy)-2- 5 methyl-2-(2R*)-phenylpiperidino)methyll-2.3-dihvdro-(4H)-3- oxo-1.2_4-triazole TMs was prepared from the compoτmd of Description 28 according to the procedure outiined in Example 3δ. Η NMR (360MHz, MeOD) δ 1.43 (3H, s, CH 3 ), 1.46 (IH, m), 1.91 (3H, m), 2.67 (2H, m), 2.98 (IH, d, J=lδHz, NCHHtriazolone), 3.21 (2H, m), 3.δ8 (IH, d, J=lδHz, NCHH triazolone), 3.72 (IH, d, J=12Hz, OCHH), 4.36 (IH, d, J=12Hz, OCHH), 7.18 (IH, t, 5 ArH), 7.2δ (2H, t, ArH), 7.37 (2H, s, ArH), 7.63 (IH, s, ArH), 7.56 (IH, s, ArH), 7.71 (IH, s, ArH). EXAMPLE 8 10 5-rf(2S.3SV3-((3.5-Bisftrifluoromethyl)phenyl)methyloxy)-2- (3-fluorophenyl)piperidino}methvn2.3-dihvdro-(4H')-3-oxo-1.2.4- triazole Η NMR (CDC1 3 ) δ 1.42-1.62 (2H, m), 1.84-2.2 (3H, m), 2.86- lδ 3.1 (2H, m), 3.38-3.68 (3H, m), 4.08 (IH, d, J=12Hz, OCHH), 4.54 (IH, d, J=12Hz, OCHH), 6.92-7.04 (IH, m, ArH), 7.16-7.32 (3H, m, ArH), 7.54 (2H, s, ArH), 7.76 (IH, s, ArH). EXAMPLE 82 20 3-r((2S.3S -3-((3.5-Bis(trifluoromethvLphenyl methyloxy)-2- phenylpiperidino}methvn-1.2.4-triazine (a) The compound of Description 3 (lg) was dissolved in dimethylformamide (8ml) and N-t-butyloxycarbonyl-2- cMoroacetamidrazone (0.6g) was added, foUowed by potassium 25 carbonate (0.9g). The mixture was stirred at room temperature overnight. The mixture was diluted with water, extracted with ethyl acetate and the organic layer was washed with brine, dried (MgS0 4 ) and evaporated. The residue was purified by column chromatography on siHca using ethyl acetate as eluant. 30 TMs afforded the compound as a wMte soHd wMch was recrystaUised from ether-hexane. Η NMR (360MHz, CDC1 3 ) δ 1.40 (9H, s, (CH 3 ) 3 ), 1.42-1.6 (3H, m), 2.13-2.2 (2H, m), 2.62 (IH, d, J=15Hz, NCHHC=NH), 3.07-3.10 (IH, m, CHHN), 3.36 (IH, d, J=15Hz, NCHHC=NH), 3.38 (IH, s, CHO), 3.57 (IH, brs, CHPh), 4.02 (IH, d, J=12Hz, OCHH), 4.45 (IH, d, J=12Hz, OCHH), 7.25-7.40 (5H, m, ArH), 7.53 (2H, s, ArH), 7.73 (IH, s, ArH). (b) The Boc-protected amidrazone (lg) was dissolved in methanoHc hydrogen cMoride and stirred for 12h. The solvent was evaporated and the crude product was used in subsequent reactions without further purification. (c) The amidrazone hydrocMoride of (b) above (200mg) was dissolved in ethanol (2ml). Magnesium sulphate was added (lOOmg) and the mixture stirred for 30min. Triethylamine (0.06ml) was added foUowed by glyoxal (90mg, trimeric dihydrate). TMs mixture was aUowed to stir for 12h. The solvent was removed in vacuo and the residue was dispersed between ethyl acetate and water. The orgamc layer was dried (MgS0 4 ) and concentrated to afford a brown oil. TMs was purified by column chromatography on siHca using hexane in ethyl acetate (95%) to afford the title compound. Η NMR (360MHz, CDC1 3 ) δ 1.53-1.72 (2H, m, CH 2 ), 1.98-2.22 (2H, m, CH 2 ), 2.42-2.53 (IH, m, NCHH), 3.14-3.22 (IH, m, NCHH), 3.61 (IH, bs, CHO), 3.74- 3.81 (2H, m, NCHPh + OCHH), 4.04 (IH, d, J=12Hz, NCHHtriazine), 4.19 (IH, d, J=12Hz, OCHH), 4.47 (IH, d, J=12Hz, NCHHtriazine), 7.24-7.37 (4H, m, ArH), 7.48-7.6 (4H, m, ArH), 7.70 (IH, s, ArH), 8.6 (IH, s, ArH). MS (CI+) m/z 497 (M++1, 100%). The following examples illustrate pharmaceutical compositions according to the invention. T.YAMPT.T. SIR Tablets containing 1-25mσ of compound Compound of formula (I) Microcrystalline cellulose Modified food corn starch Lactose Magnesium Stearate EXAMPT.T: 83B Tablets containing 26-100mσ of compound mount m Compound of formula (I) Microcrystalline cellulose Modified food corn starch Lactose Magnesium Stearate The compound of formula (X) , cellulose, lactose and a portion of the corn starch are mixed and granulated with 10% corn starch paste. The resulting granulation is sieved, dried and blended with the remainder of the corn starch and the magnesium stearate. The resulting granulation is then compressed into tablets containing l.Omg, 2.0mg, 25.0mg, 26.0mg, 50.0mg and lOOmg of the active compound per tablet. • RYΆMPT.T; SA arenteral injection Amount mg Compound of formula (I) 1 to lOOmg Citric Acid Monohydrate 0.75mg Sodium Phosphate 4.5mg Sodium Chloride 9mg Water for Injections to 1ml - Ill - The sodium phosphate, citric acid monohydrate and sodium chloride are dissolved in a portion of the water. The compound of formula (I) is dissolved or suspended in the solution and made up to volume. EXAMPLE 85 Topical formulation Amount mg Compound of formula (I) 1-lOg Emulsifying Wax 30g Liquid paraffin 20g White Soft Paraffin to lOOg The white soft paraffin is heated until molten. The liquid paraffin and emulsifying wax are incorporated and stirred until dissolved. The compound of formula (I) is added and stirring continued until dispersed. The mixture is then cooled until solid.

Claims: CLAIMS: 1. A compound of formula (I) , or a salt or prodrug thereof: (I) wherein n is 1, 2 or 3; X represents 0 or S; Y represents a hydrocarbon chain of 1, 2 , 3 or 4 carbon atoms which may optionally be substituted by oxo; R 1 represents phenyl optionally substituted by 1, 2 or 3 groups selected from Ci-galkyl, C2-6 alkenyl, C2-6al ynyl, halo, cyano, nitro, trifluoromethyl, trimethylsilyl, -OR a , SR a , SOR a , S0 2 R a , -NR a R b , -NR a COR b , -NR a C0 2 R b / -C0 2 R a or -CONR R b ; R 2 represents aryl selected from phenyl and naphthyl; heteroaryl selected from indazolyl, thienyl, furyl, pyridyl, thiazolyl, tetrazolyl and quinolyl; benzhydryl; or benzyl; wherein each aryl or heteroaryl moiety may be substituted by Ci-gal yl, Cj-sal o y, halo or trifluoromethyl; R 4 and R 5 may be present on any available carbon atom of the azacyclic ring and each independently represent H, halo, Ci-galkyl, oxo, CH 2 OR a , C0 2 R a or CONR a R b ; R 8 represents an optionally substituted aromatic heterocycle; and R a and R b each independently represent H, trifluoromethyl, or phenyl optionally substituted by Ci-galkyl, halo or trifluoromethyl. 2. A compound as claimed in claim 1 of formula (IA) (IA) wherein n is 1, 2 or 3 and any carbon atom of (CH 2 ) n may be substituted by R 12 and/or R 13 ; X represents O or S; R 10 represents phenyl optionally substituted by 1, 2 or 3 groups selected from Ci-galkyl, C2-6 alkenyl, C _salkynyl, halo, cyano, nitro, trifluoromethyl, trimethylsilyl, -OR c , SR C , SOR c , S0 2 R c , -NR c R d , -NR c COR d , -NR c C0 2 R d , -C0 2 R c or -CONR c R d ; R 11 represents aryl selected from phenyl and naphthyl; heteroaryl selected from indazolyl, thienyl, furyl, pyridyl, thiazolyl, tetrazolyl and quinolyl; benzhydryl; or benzyl; wherein each aryl or heteroaryl moiety may be substituted by C^-gallyl, Ci-galkoxy, halo or trifluoromethyl; R 12 and R 13 each independently represent H, halo, Ci-ealkyl, oxo, C0 2 R c or CONR^* 1 ; R 14 represents Cι_ alkyl, optionally substituted by oxo, substituted by an optionally substituted aromatic heterocycle; and R c and R d each independently represent H, Cι_galkyl, phenyl optionally substituted by Ci-galkyl, or halo or trifluoromethyl; or a salt or prodrug thereof. 3. A compound as claimed in claim 2 wherein n is 2 or 3; R 12 and R 13 each independently represent H, halo, C -galkyl, C0 R c or C0NR c R d ; R 14 represents Cι_ 4alkyl substituted by an optionally substituted 5- or 6- membered aromatic heterocycle; and R c and R d each independently represent H, Ci-galkyl, phenyl or trifluoromethyl. 4. A compound as claimed in any preceding claim wherein R 1 represents phenyl substituted by one or more groups selected from Cι_4alkyl, trifluoromethyl and halo. 5. A compound as claimed in any preceding claim wherein R 2 represents benzhydryl or optionally substituted phenyl. 6. A compound as claimed in any preceding claim wherein R 8 represents optionally substituted thienyl, furyl, pyridyl, triazolyl, tetrazolyl, thiazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, oxazolyl, oxadiazolyl, thiadiazolyl, imidazolyl, benzimidazolyl or benzoxazolyl. 7. A compound as claimed in any of claims 1 to 5 wherein R 8 represents a substituted or unsubstituted 5- or 6-membered nitrogen-containing aromatic heterocycle. 8. A compoτmd as claimed in claim 7 wherein R 8 represents optionally substituted oxazolyl, oxadiazolyl, imidazolyl, thiadiazolyl, triazolyl, pyrazinyl, pyrimidinyl, pyridazinyl or triazinyl, or tetrazolyl substituted by Ci-galkyl. 9. A compound as claimed in claim 8 wherein R represennttss uunnssuubbssttiittuutteedd tt:riazolyl or triazolyl substituted by oxo or thioxo. 10. A compound as claimed in any preceding claim wherein n is 3. 11. A compound as claimed in claim 1 selected from: 3-amino-5-[ ((2R*,3R*)-3-((3,5-bis(trifluoromethyl)phenyl) methyloxy)-2-phenylpiperidino)methyl]-1,2,4-oxadiazole; 5-[((2R*,3R*)-3-((3,5-bis(trifluoromethyl)phenyl) methyloxy)-2-phenylpiperidino)methyl]-3-methyl-l,2,4- oxadiazole; (+)-3-amino-5-[ ((2S,3S)-3-((3,5-bis(trifluoromethyl) phenyl)methyloxy)-2-phenylpiperidino)methyl]-1,2,4- oxadiazole; 3-[((2R*,3R*)-3-((3,5-bis(trifluoromethyl)phenyl) methyloxy)-2-phenylpiperidino)methyl]pyridine; 2-[((2R*,3R*)-3-((3,5-bis(trifluoromethyl)phenyl) methyloxy)-2-phenylpiperidino)methyl]pyridine; 2-C((2R*,3R*)-3-((3,5-bis(trifluoromethyl)phenyl) methyloxy)-2-phenylpiperidino)methyl]benzimidazole; 5-[((2R*,3R*)-3-((3,5-bis(trifluoromethyl)phenyl) methyloxy)-2-phenylpiperidino)methyl]tetrazole; 2-[((2R*,3R*)-3-((3,5-bis(trifluoromethyl)phenyl) methyloxy)-2-phenylpiperidino)methyl]-4-methyl-1,3- thiazole; (2R*,3R*)-3-((3,5-bis(trifluoromethyl)phenyl)methyloxy)- 1-(2-furoyl)-2-phenylpiperidine; 2-[((2R*,3R*)-3-((3,5-bis(trifluoromethyl)phenyl) methyloxy)-2-phenylpiperidino)methyl]furan; 5- 1((2R*,3R*)-3-((3,5-bis(trifluoromethyl)phenyl) methyloxy)-2-phenylpiperidino)methyl]-3-bromo-l,2,4- oxadiazole; 5-[((2R*,3R*)-3-((3,5-bis(trifluoromethyl)phenyl) methyloxy)-2-phenylpiperidino)methyl]-3-dimethylamino- 1,2,4-oxadiazole; (2R*,3R*)-3-((3,5-bis(trifluoromethyl)phenyl)methyloxy)- 2-phenyl-l-(2-thienoyl) iperidine; (2R ,3R )-3-((3,5-bis(trifluoromethyl)phenyl)methyloxy)- 2-phenyl-l-(2-thienyl)methylpiperidine; 5-[((2R*,3R*)-3-((3,5-bis(trifluoromethyl) henyl) methyloxy)-2-phenylpiperidino)methyl]-2,3-dihydro-4- methyl-3-thioxo-l,2,4-triazole; 3-[((2R*,3R*)-3-((3,5-bis(trifluoromethyl)phenyl) methyloxy)-2-phenylpiperidino)methyl]-1,2,4-triazole; 5-[((2R*,3R*)-3-((3,5-bis(trifluoromethyl)phenyl) methyloxy)-2-phenylpiperidino)methyl]-2,3-dihydro-(4H)-3- thioxo-1,2,4-triazole; 5-[((2R*,3R*)-3-((3,5-bis(trifluoromethyl) phenyl)methyloxy)-2-phenylpiperidino)methyl]-2- methyltetrazole; 5-[((2R*,3R*)3-((3,5-bis(trifluoromethyl) phenyl)methyloxy)-2-phenylpiperidino) ethyl]-1- methyltetrazole; 3-[((2R*,3R*)-3-((3 ,5-bis(trifluoromethyl)phenyl) methyloxy)-2-phenylpiperidino)methyl]-5-dimethylamino- 1,2,4-thiadiazole; 2-[ ((2R*,3R*)-3-((3,5-bis(trifluoromethyl)phenyl) methyloxy)-2-phenylpiperidino)methyl]-4,7- dimethylbenzoxazole; 2-[((2R*,3R*)-3-((3,5-bis(trifluoromethyl)phenyl) methyloxy)-2-phenylpiperidino)methyl]benzoxazole; 4-C ((2S,3S)-3-((3,5-bis(trifluoromethyl) phenyl)methyloxy)-2-phenylpiperidino)methyl]oxazole; 2-[((2S,3S)-3-((3,5-bis(trifluoromethyl) phenyl)methyloxy)-2-phenylpiperidino)methyl]pyrazine; 4-[((2S,3S)-3-((3,5-bis(trifluoromethyl) phenyl)methyloxy)-2-phenylpiperidino)methyl]-2-methyl- 1,3-thiazole; 3-[((2S,3S)-3-((3,5-bis(trifluoromethyl) phenyl)methyloxy)-2-phenylpiperidino)methyl]-1,2,4- oxadiazole; 3-[((2S,3S)-3-((3,5-bis(trifluoromethyl) phenyl)methyloxy)-2-phenylpiperidino)methyl]-5-iodo- 1,2,4-thiadiazole; 3-[((2S,3S)-3-((3,5-bis(trifluoromethyl) phenyl)methyloxy)-2-phenylpiperidino)methyl]-1,2,4- thiadiazole; 3-[((2S,3S)-3-((3,5-bis(trifluoromethyl) phenyl)methyloxy)-2-phenylpiperidino)methyl]-5-methoxy- 1,2,4-thiadiazole; 3-[((2S,3S)-3-((3,5-bis(trifluoromethyl)phenyl) methyloxy)-2-phenylpiperidino)methyl]-1,2,4-triazole; 5-C((2S,3S)-3-((3,5-bis(trifluoromethyl)phenyl) methyloxy)-2-phenylpiperidino)methyl]-2,3-dihydro-(4H)-3- thioxo-1,2,4-triazole; 2-[( (2S,3S)-3-((3,5-bis(trifluoromethyl)phenyl) methyloxy)-2-phenylpiperidino)methyl]-1-(£- toluenesulphonyl)imidazole; 2-[((2S,3S)-3-((3,5-bis(trifluoromethyl)phenyl) methyloxy)-2-phenylpiperidino)methyl]imidazole; 4-[((2S,3S)-3-((3,5-bis(trifluoromethyl) henyl) methyloxy)-2-phenylpiperidino)methyl]imidazole; 5-[((2R*,3R*)-3-((3,5-bis(trifluoromethyl)phenyl) methyloxy)-2-phenylpiperidino)methyl]-2,3-dihydro-(4H)-3- oxo-l,2,4-triazole; 5-[((2R*,3R*)-3-((3,5-bis(trifluoromethyl) henyl) methyloxy)-2-phenylpiperidino)methyl]-3-(N,N- dimethylamino)-l,2,4-thiadiazole; 5-[((2S,3S)-3-((3,5-bis(trifluoromethyl)phenyl) methyloxy)-2-phenylpiperidino)methyl]tetrazole; 5-[((2S,3S)-3-((3,5-bis(trifluoromethyl)phenyl) methyloxy)-2-phenylpiperidino)methyl]-2-methyltetrazole; 5-X((2S,3S)-3-((3,5-bis(trifluoromethyl)phenyl) methyloxy)-2-phenylpiperidino)methyl]-1-methyltetrazole; 3-[((2S,3S)-3-((3,5-bis(trifluoromethyl)phenyl) methyloxy)-2-phenylpiperidino)methyl]pyridazine; 2-[((2S,3S)-3-((3,5-bis(trifluoromethyl)phenyl) methyloxy)-2-phenylpiperidino)methyl]-1,3,5-triazine; 5-[((2S,3S)-3-((3-t-butyl-5-methylphenyl)methyloxy)-2- phenylpiperidino)methyl]-2,3-dihydro-(4H)-3-oxo-l,2,4- triazole; 2-[((2S,3S)-3-((3,5-dichlorophenyl)methyloxy)-2- phenylpiperidino)methyl]imidazole; 5-[((2S,3S)-3-((3-chloro-5-methylphenyl)methyloxy)-2- phenylpiperidino)methyl]-2,3-dihydro-(4H)-3-oxo-1,2,4- triazole; ~~ 5-[((2S,3S)-3-((3,5-bis(trifluoromethyl)phenyl) methyloxy)-2-diphenyl ethyl)pyrrolidino)methyl]-2,3- dihydro-(4H)-3-oxo-l,2,4-triazole; 5-[((2R,3S)-3-((3,5-bis(trifluoromethyl) phenyl)methyloxy)-2-diphenylmethyl)pyrrolidino)methyl]- 2,3-dihydro-(4H)-3-oxo-l,2,4-triazole; 3-[((2S,3S)-3-((3,5-dichlorophenyl)methyloxy)-2- diphenylmethyl)pyrrolidino)methyl]-1,2,4-triazole; 5-[((2S,3S)-3-((3-t-butyl-5-chlorophenyl)methyloxy)-2- phenylpiperidino) ethyl]-2,3-dihydro-(4H)-3-oxo-l,2,4- triazole; 5-[ ((2S,3S)-3-((3,5-bistrifluoromethyl) henyl)methyloxy)- 2-phenylpiperidino)methyl]-2,3-dihydro-(4H)-3-oxo-l,2,4- triazole; 3-[((2S,3S)-3-((3,5-bistrifluoromethyl)phenyl)methyloxy)- 2-phenylpiperidino)methyl]-1-methyl-l,2,4-triazole; 3-[((2S,3S)-3-((3,5-bistrifluoromethyl)phenyl)methyloxy)• 2-phenylpiperidino)methyl]-5-phenyl-l,2,4-oxadiazole; 3-C((2R*,3R*)-3-((3,5-bistrifluoromethyl)phenyl) methyloxy)-2-phenylpiperidino)methyl]-5-thiomethyl-l,2,4- triazole; 5-[ ((2S,3S)-3-((3,5-dichlorophenyl)methyloxy)-2- phenylpiperidino)methyl-2,3-dihydro-(4H)-3-oxo-l,2,4- triazole; 4- ((2R*,3R*)-3-((3-carbomethoxyphenyl)methyloxy)-2- phenylpiperidino)methyl]pyridine; 4-[ ((2R*,3R*)-3-((3-carboxamidophenyl)methyloxy)-2- phenylpiperidino)methyl]pyridine; 5-[((2R*,3R*)-3-((2-methoxy-3-nitrophenyl)methyloxy)-2- phenylpiperidino)methyl]-3-methyl-l,2,4-oxadiazole; 3-amino-5-[((2R*,3R*)-3-((5-amino-2- methoxyphenyl)methyloxy)-2-phenylpiperidino)methyl]- 1,2,4-oxadiazole; 6-[((2S,3S)-3-((3,5-bis(trifluoromethyl)phenyl) methyloxy)-2-phenylpiperidino)methyl]uracil; 3-[((2R*,3R*)-3-((3,5-bis(trifluoromethyl) phenyl)methyloxy)-2-phenylpiperidino)methyl]-5- carboxamido-1,2,4-triazole; 3-[((2R*,3R*)-3-((3,5-bis(trifluoromethyl) phenyl)methyloxy)-2-phenylpiperidino)methyl]-5-cyano- 1,2,4-triazole; 3-[(IS)-1-((2S,3S)-3-((3,5-dichlorophenyl)methyloxy)-2- phenylpiperidino)ethyl]-1,2,4-triazole; 3-[(1R)-1-((2S,3S)-3-((3,5-dichlorophenyl)methyloxy)-2- phenylpiperidino)ethyl]-1,2,4-triazole; . 3-[((2S,3S)-3-((2,3-dimethylphenyl)methyloxy)-2- phenylpiperidino)methyl]-1,2,4-triazole; 5-[((2S,3S)-3-((2,3-dimethylphenyl)methyloxy)-2- phenylpiperidino)methyl]-2,3-dihydro-(4H)-3-oxo-l,2,4- triazole; 5-[((2S,3S)-2-phenyl-3-((3-trifluoromethyl)phenyl) methyloxy)piperidino)methyl]-2,3-dihydro-(4H)-3-oxo- 1,2, -triazole; 5-[((2S,3S)-3-((3,4-dichlorophenyl)methyloxy)-2- phenylpiperidino)methyl]-2,3-dihydro-(4H)-3-oxo-l,2,4- triazole; 5-[((2S,3S)-3-((3-t-butylphenyl)methyloxy)-2- phenylpiperidino)methyl]-2,3-dihydro-(4H)-3-oxo-l,2,4- triazole; 5-[((2R*,3R*)-3-((3,5-dimethylphenyl)methyloxy)-2- phenylpiperidino)methyl]-2,3-dihydro-(4H)-3-oxo-l,2,4- triazole; (2S,3S)-3-((3,5-bis(trifluoromethyl)phenyl)methyloxy)-2- phenyl-1-(3-(1,2,4-triazolyl))piperidine; (2S,3S)-3-((3,5-bis(trifluoromethyl)phenyl)methyloxy)-1- (l-oxo-2-pyrid-4-yl)ethyl-2-phenylpiperidine; (2S,3S)-3-((3,5-bis(trifluoromethyl)phenyl)methyloxy)-1- (2-oxo-2-pyrid-3-yl)ethyl-2-phenylpiperidine; 3-(IS)-1-((2S,3S)-3-((3,5-bis(trifluoromethyl)phenyl) methyloxy)-2-phenylpiperidino)ethyl]-1,2,4-triazole; 3-(1R)-1-((2S,3S)-3-((3,5-bis(trifluoromethyl)phenyl) methyloxy)-2-phenylpiperidino)ethyl]-1,2,4-triazole; 5-(IS)-1-((2S,3S)-3-((3,5-bis(trifluoromethyl)phenyl) methyloxy)-2-phenylpiperidino)ethyl]-2,3-dihydro-(4H)-3- oxo-1,2,4-triazole; 3-C ((2S,3S)-3-((3,5-dichlorophenyl)methyloxy)-2- phenylpiperidino)methyl]-1,2,4-triazole; 5-[((2R*,3R*)-3-((3,5-bis(trifluoromethyl)phenyl) methyloxy)-2-(3-chlorophenyl)piperidino)methyl]-2,3- dihydro-(4H)-3-oxo-l,2,4-triazole; 5-[ ((2S,3S)-3-((3,4-dimethylphenyl)methyloxy)-2- phenylpiperidino)methyl]-2,3-dihydro-(4H)-3-oxo-l,2,4- triazole; 5-[((2S,3S)-3-((3-i-propoxyphenyl)methyloxy)-2- phenylpiperidino)methyl]-2,3-dihydro-(4H)-3-oxo-l,2,4- triazole; - 5-[ ((2S,3S)-3-((3-fluoro-5-methylphenyl)methyloxy)-2- phenylpiperidino)methyl]-2,3-dihydro-(4H)-3-oxo-l,2,4- triazole; 5-[(3-(3R*)-((3,5-bis(trifluoromethyl)phenyl)methyloxy)- 2-methyl-2-(2R*)-phenylpiperidino)methyl-2,3-dihydro- (4H)-3-oxo-l,2,4-triazole; 5-[((2S,3S)-3-((3,5-bis(trifluoromethyl)phenyl) methyloxy)-2-(3-fluorophenyl)piperidino)methyl]-2,3- dihydro-(4H)-3-oxo-l,2,4-triazole; 3-[((2S,3S)-3-((3,5-bis(trifluoromethyl)phenyl) methyloxy)-2-phenylpiperidino)methyl]-1,2,4-triazine; and salts and prodrugs thereof. 12. A process for the preparation of a compound as claimed in claim 1, which process comprises: (A) reacting a compound of formula (II) : ( ID wherein R 1 , R 2 , R 4 , R 5 , X and n are as defined for formula (I) , with a reagent suitable to introduce the group Y-R 8 ; or (B) reacting a compound of formula (III) with a compound of formula (IV) : ~" wherein R 1 , R 2 , R 4 , R 5 , X, Y and n are as defined for formula (I) , R 30 represents an alkyl group and R 31 represents-!! or a suitable substituent, in the presence of a base; or (C) reacting a compound of formula (V) : (V) wherein R 1 , R 2 , R 4 , R 5 , X, Ϋ and n are as defined for formula (I) , with an alkali metal azide; or (D) reacting a compound of formula (VI) : (VI) wherein R 1 , R 2 , R 4 , R 5 , X, Y and n are as defined for formula (I) , with a compound of formula Hal-CH 2 C(=O)R 60 / where Hal represents halo and R 60 represents H or a suitable substituent; or (E) reacting a compound of formula (VII) : wherein R 1 ,JH 2 , R 4 , R 5 , X, Y and n are as defined for formula (I) , with a compound of formula R 61 NCS, wherein R 61 is H or a suitable substituent, in the presence of a base; or - (F) reacting a compound of formula (II) as previously defined with a compound of formula (VIII) : α (VI I I ) wherein Y and Hal are as previously defined and R 18 is H or a group suitable as a substituent of the triazole ring, or convertible to such a group under the reaction conditions, in the presence of a base; or (G) reacting a compound of formula (IX) : (IX) wherein R 1 , R 2 , R 4 , R 5 , X, Y and n are as defined for formula (I) , with a substituted or unsubstituted triazine; or (H) reacting a compound of formula (X) with a compound of formula (XI) : (X) (XI) wherein R 1 , R 2 , R 4 , R 5 , X, Y and n are as defined for formula (I) and R 35 and R 36 each independently represent H or a suitable. substituent. 13. A process as claimed in claim 12 wherein, for (A) or (F) , the base is an alkali metal carbonate. 14. A process as claimed in claim 12 or claim 13 wherein, for (A) , the reagent suitable to introduce the group Y-R 8 is R 8 -Y-L where L is chloro, bromo, iodo, methylsulphonate or p-toluenesulphonate. 15. A process as claimed in claim 12 wherein, for (B) , the base is an alkali metal or an alkali metal hydride. 16. A process as claimed in claim 12 wherein, for (C) , the alkali metal azide is sodium azide and the reaction is effected in N-methylpyrrolidinone as solvent. 17. process as claimed in claim 12 wherein, for (D) , R 60 is H or C!_ 6 alkyl. 18. A process as claimed in claim 12 wherein, for (E) , the base is l,8-diazabicyclo[5.4.0]undec-7-ene. 19. A process as claimed in claim 12 wherein, for (F), R 18 is methoxy. 20. A process as claimed in claim 12 wherein, for (G) , the reaction temperature is 80-90*C. 21. A process as claimed in claim 12 wherein, for (H) , R 35 and R 36 each represent H. 22. A compound as claimed in any one of claims 1 to 11 for use in therapy. 23. A pharmaceutical composition comprising a compound as claimed in any one of claims 1 to 11 in association with a pharmaceutically acceptable carrier. 24. A pharamaceutical composition as claimed in claim 23 further comprising a bronchodilator. 25. A method for the treatment or prevention of a physiological disorder associated with an excess of tachykinins, which method comprises administration to a patient in need thereof of a tachykinin-reducing amount of a compound according to claim 1. 26. Amethod according to claim 25 for the treatment or prevention of pain or inflammation. 27. A method according to claim 25 for the treatment or prevention of migraine. 28. A method according to claim 25 for the treatment or prevention of arthritis. 29. A method according to claim 25 for the treatment or prevention of postherpetic neuralgia. 30. A method for the treatment of a respiratory disease, which method comprises administration to a patient in need thereof of an effective amount of a compound as claimed in claim 1 and an effective amount of a bronchodilator. 31. The use of a compound as claimed in any one of claims 1 to 11 for the manufacture of a medicament for the treatment of a physiological disorder associated with an excess of tachykinins. 32. The use of a compound as claimed in any one of claims 1 to 11 for the manufacture of a medicament for the treatment of pain or inflammation. 33. A compound as claimed in any of claims 1 to 11 when prepared by the process of claim 12. 34. A process for preparing a composition as claimed in claim 23 which process comprises bringing a compound as claimed in any of claims l to 11 into association with a pharmaceutically acceptable carrier. 35. A compound, composition or process as claimed in any one of the preceding claims, substantially as herein before described.

Inventors: BAKER RAYMOND, LADDHWAHETTY TAMARA, SEWARD EILEEN MARY, SWAIN CHRISTOPHER JOHN, BAKER, RAYMOND, LADDHWAHETTY, TAMARA, SEWARD, EILEEN MARY, SWAIN, CHRISTOPHER, JOHN
Applicants: BAKER RAYMOND, LADDHWAHETTY TAMARA, MERCK SHARP & DOHME, SEWARD EILEEN MARY, SWAIN CHRISTOPHER JOHN, MERCK SHARP & DOHME LIMITED
Application year: 1993
Main classification: C07D413
IPC codes: A61K31, A61P11, C07D207, C07D211, C07D401, C07D403, C07D405, C07D409, C07D413, C07D417