CA2133077A1 - Azacyclic compounds - Google Patents

Azacyclic compounds

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Publication number
CA2133077A1
CA2133077A1 CA002133077A CA2133077A CA2133077A1 CA 2133077 A1 CA2133077 A1 CA 2133077A1 CA 002133077 A CA002133077 A CA 002133077A CA 2133077 A CA2133077 A CA 2133077A CA 2133077 A1 CA2133077 A1 CA 2133077A1
Authority
CA
Canada
Prior art keywords
methyloxy
phenyl
methyl
trifluoromethyl
phenylpiperidino
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
Application number
CA002133077A
Other languages
French (fr)
Inventor
Raymond Baker
Tamara Ladduwahetty
Eileen Mary Seward
Christopher John Swain
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Organon Pharma UK Ltd
Original Assignee
Individual
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from GB929208323A external-priority patent/GB9208323D0/en
Priority claimed from GB929216065A external-priority patent/GB9216065D0/en
Priority claimed from GB929219686A external-priority patent/GB9219686D0/en
Priority claimed from GB929226069A external-priority patent/GB9226069D0/en
Application filed by Individual filed Critical Individual
Publication of CA2133077A1 publication Critical patent/CA2133077A1/en
Abandoned legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/08—Bronchodilators
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/12—Oxygen or sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/54—Sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

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;
R1 is phenyl optionally substituted by 1, 2 or 3 of C1-6alkyl, C2-6alkenyl, C2-6alkynyl, halo, cyano, nitro, trifluoromethyl, trimethylsilyl, -ORa, SRa, SORa, SO2Ra, -NRaRb, -NRaCORb, -NRaCO2Rb, -CO2Ra or -CONRaRb; R2 is phenyl, indazolyl, thienyl, furyl, pyridyl, thiazolyl, tetrazolyl, quinolyl, benzhydryl, or benzyl; R4 and R5 each independently represent H, halo, C1-6alkyl, oxo, CH2ORa, CO2Ra or CONRaRb; R8 represents an optionally substituted aromatic heterocycle; and Ra and Rb are H, trifluoromethyl, C1-6alkyl or phenyl optionally substituted by C1-6alkyl, halo or trifluoromethyl; are tachykinin antagonists useful in medecine.

Description

2 1 3 ~ Q 7 ~
WO93/21181 PCT/GB93/0078~

AZACYC~IC CO~PO~ND8 ThiC invention relates to a class of azacyclic 5 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 nervou~a system and in the peripheral nervous and circulatory systems.
The structures of three known mammalian tachykinins are as follows:
Substan e P:
Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-~ly-~eu-Net-NK2 Neurokinin A:
His-Lys-Thr-Asp-Ser-Phe-Val-&ly-Leu-Met-NH2 Neurokinin B:
Asp-Met-His-Asp-Phe-Phe-Val-Gly-Leu-Met-NH2 For example, substance P i~ believed inter alia to ~e involved in th~ neurotransmission of pain sensations ~Otsuka et ~ 'Role of Substance P as a Sensory Transmitter in 5pinal Cord and Sympathetic Gangl ia" in 1982 Substance P in the Nervous System, Ciba Foundation Symposium 91, 13-34 (published by Pitman) and Otsuka and Yanagisawa, "Does Subs~anc@ 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 arthri~ Levine et ~1 in Science (1984) ~ 547-54g].
These peptides have also been implicated in gas~rointestinal (GI) disorders and diseases of the GI

~ 1 v v`.3 7, WO93/21181 PCT/GB93/00788~ `

tract such as inflammatory bowel disease [Mantyh et al in Neuroscience (lg88) 2S (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 S~mme~rical Arthritis"
in The Lancet, 11 November 1989 and Gronblad et a].
"Neuropeptides in Synovium of Patients with Rheumatoid Arthritis and Osteoarthritis" in J. Rheumatol. (lC~88) 15 (12) 1807-10] r Therefore, substance P is believed to be in~olved in the inflammatory response in diseases such as rheumatoid arthritis and osteoarthritis [OIByrne et al in Arthritis and Rheumatism tl990) 33 1023-8]~ Other disease areas where tachykinin antagonists are believed to be useful are all~rgic conditions [Hamelet et al Can.
J. Pharmacol. Physiol. (1988) 66 1361-7], immunoregulation [Lotz et al Science (1988) 241 1218-21 an~ Kimball et al, J~ Immunol. (19~8) 141 ~lO) 3564-~]
vasodilation, bronchospasm, reflex or neuronal control of the viscera [Mantyh et al, PNAS ~1988) 85 3235-9] and, possibly by arresting or slowin~ ~-amyloid-mediated neurodegenerative changes [Ya~kner et al Science, (1~9O) 250, 279082] 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 presented at C.I.N.P. XVIIIth Congress, 28th June-2nd July, lg92~, and in disorders of bladder function~uch as bladder detrusor hyper-reflexia (Lancet~ 16th May, 1992, 1239).
It has furthermore been suggested that tachykinins have utility in the following disorders:

2 1 3 3 !~ ~ r~ ~.
- WO g3/21181 P~tGB93/00788 de~ression, dysthymic disorders, chronic obstructi~e 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~ neurapathy, neuralgia, disorders related to immune enhancement or suppression such as systemic lupu5 srythmatosis (European patent applicati~n 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 app}ication no. 0 394 989) and emesis (European patent application no. 0 533 2&0).
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~applicatiorl no. 0 436 334discloses 4- to 7-membered azacyclic compounds substituted at the 3-posi ion by a substituted amino moiety. The compounds are said to be tachykinin antagonists.
The present invention provides a compound of for~ula (I), or a salt or prodrug thereof:

WO93/21181 ~ 3 o 7 ~ PCT/GB93/00788 R~ ~ X ~

~ ~ R2 R Y-R~

( 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;
R1 represents phenyl optionally substituted by 1, 2 or 3 groups selected from Cl_6alkyl, C2_6 alkenyl, ~- C2_6alkynyl, halo, cyano, nitro, trifluoromethyl, ylsilyl, _ORa, SRa, soRa, SO~a, _NRaRb, _NRacORb ~- 20 -NRaCO2Rb, -CO2Ra or - ONRa~ ;
R2 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 substi~uted by Cl_6alkyl, Cl_6alkoxy, halo or trifluoromethyl;
R4 and R5 may be present on any available carbon atom of the azacyclic ring and each independently represent H, halo, Cl_6alkyl, oxo, CH2ORa, C02Ra or CONR~ * ;
R8 represents an optionally substituted aromatic heterocycle; and 2 3 ~ 0 7 7 WOg3/21181 PCT/GB93/00788 Ra and Rb each independently represent H, trifluoromethyl, C1_6alkyl or phenyl optionally substituted ~y Cl_6alkyl, 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 s~raight, 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 ~erm "halo'l as used herein includes fluoro, chloro, bro~o and iodo, especially chloro and fluoroO `
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 form~la (I) which are readily convertible in vivo into the required compound of formula (I). Conventional procedures for the selection and preparation of suitable prodrug deri~atives are described, for example, in "Design of Prodrugs", ed. H~
Bundgaard, ElseYier, 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 c~
stereochemistry is preferred. It is to be understood ~l~J~ J ~:3 7 3 ~
2~077 ; -` 19'34 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 CH2, C=0, CH(CH3), CH2(C=0) or (C=O)CH2. 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(CH3).
Preferably R1 represents substituted phenyl.
When R1 is substituted phenyl suitable substituents include nitro, trifluoromethyl, trimethylsilyl, bromo, chloro, fluoro, iodo, cyano, Cl_6alkyl such as methyl, - ~thyl, i-propyl, i-butyl, t-butyl and cyclopropyl, C2 6alkenyl such as vinyl, ~1_6alkoxy such as methoxy, ethoxy and i-propoxy, phenoxy, amino, carboxamido and methoxycarbonyl. Preferably Rl represents phenyl substi~uted by one or more groups selected from C1_4alkyl, such as methyl and t-butyl, trifluoromethyl and halo such as iodo, bromo chloro and fluoro.
Suitably Rl represe~ts monosubstituted phenyl, such as 3-substituted phenyl or, preferably, disubstituted phenyl, such as 3,5-disubstituted phenyl.
Preferably Rl represents phenyl substituted at the 3-position by trifluoromethyl or a C1_6alkyl 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 R1 include 3,5-bis(trifluoromethyl~phenyl, 3,5-dichlorophenyl, 3-t-butyl-5-me~hylphenyl, 3-chloro-5-methylphenyl, 3-t-butyl-5-chlorophenyl, 3-bis(trifluoromethyl)phenyl and 3-t-; . ... . ..... ... .. ~

WO93/21181 2 ~ 3 3 ~'~ 7 i PCT/GB93/00788 butylphenyl. Particularly preferred is 3,5-bis(trifluoromethyl)phenyl.
Suitably R2 represents benzhydryl or optionally substituted phenyl, such as phenyl optionally substituted by halo such as fluoro or chloro, preferably in the 3-position. Preferably R2 represents unsubstituted phenyl or unsubstituted benzhydryl, more pre~erably unsubstituted phenyl.
Suitable values for R4 and R5 include H, Cl_6alkyl, especially methyl, hydroxymethyl and oxo. The substitutents R4 and R5 may be located on any available car~on atom of the azacyclic ring including, except in the case where the substituent R4 or R5 in question represents oxo, C-2 and C-3. Preferably at least one of R4 and R5 represents H. In one preferred group of compounds R4 and R5 both represent H. In a further preferred group of co~pounds one of R4 and R5 is H and the other of R4 and R5 is methyl, preferably ~-methyl.
When R8 represents a substituted aromatic heterocycle, suitable substi~uents in the heterocyclic ring include one or more of Cl_6alkyl, Cl_6alkoxy, phenyl, oxo, thioxo, halo, trifluoromethyl, MRaRb, NRaCORb, CONRaRb, C02Ra, SRa, S02Ra and CH20Ra, where Ra and Rb are as previously defined. Particular examples of suitab~e substituents include methyl, methoxy, phenyl, oxo, thioxo, bromo, iodo, NH2, SCH3, CONH2 and cyano.
Particularly preferred substituents include oxo a~d NH2.
Suitable values for R8 include thienyl, furyl, pyrrolyl, pyridyl, pyrazolyl, triazolyl, tetrazolyl, ~hiazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, oxazolyl, oxadiazolyl, thiadiazolyl, isoxazolyl, quinolyl, isothiazolyl, imidazolyl, benzimidazolyl, benzoxazolyl, benzothiophenyl, 2 ' ? ~ Q7 ~
WO9t/21181 PCT/GB93/00788 benzofuranyl and indolyl, any of which may be substituted~
In particular, R8 may represent optionally substituted thienyl, furyl, pyridyl; triazolyl, tetrazolyl, thiazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, oxazolyl, oxadiazolyl, thi~diazolyl, imidazolyl, benzimidazolyl or benzoxazolyl~
In ohe group of compounds a~cording to the invention R8 represents optionally substituted pyrrolyl, pyrazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, oxadiazolyl, thiadiazolyl, imidazolyl, benzimidazolyl, benzoxazolyl, benzothiophenyl, benzofuranyl or indolyl.
Preferably R8 represents a substituted or unsubstituted 5- or 6-m~mbered nitrogen containing aromatic heterocycle such as for example oxazolyl, oxadiazolyl, tetrazolyl, thiazolyl, thiadiazolyl, triazolyl, pyrazinyl, pyridyl, pyrimidinyl, pyridazinyl, imidazolyl or triazinyl. More preferably R8 reDresents optionally substituted oxazolyl, oxadiazolyl, imidazolyl, thiadiazolyl, triazolyl, pyrazinyl, pyrimidinyl, pyridazinyl or triazinyl, or tetrazolyl substituted by Cl_6alkyl, preferably methyl.
In one preferred group of compounds according to the invention, R8 represents substituted or unsubstituted oxadiazolyl, for example, oxadiazolyl substituted by halo, amino, dialkylamino or methyl. More preferably R8 represents 5-(3-aminooxadiazolyl).
In a further preferred group of compounds according to the invention, R8 represents substituted or unsubstituted triazolyl~ for example, unsubstituted triazo~yl or triazolyl subtituted by oxo or thioxo, more preferably, triazolyl substituted by oxo.

2 1 3 ~ ~, 7 ~

It will be appreciated that, when the heterocyclic moiety R8 is substituted by an oxo or thioxo substituent, different tautomeric forms are possible so that the substituent may be represented as =O or -OH, or 5 =S or -SH, respectively. For the avoidance of doubt, all such tautomeric forms ar~ embraced by the present invention.
One subgroup of compounds according to the invention is represented by compounds of ~ormula (~A), 10 and salts and prodrugs thereof:

R l~4 (IA) ~ 20 wherein :~ - n is l, 2 or 3 and where any carbon atom of (CH2)n may be substituted by Rl2 and/or Rl3;
: X represents O or S;
R`lO represents phenyl optionally substituted by - : 25 l, 2 or 3 groups:selected from Cl_~alkyl, C2_6 alkenyl, C2_6alkynyl, halo, cyano, nitro, trifluoromethyl, trimethylsilyl, -OR~, SRC, SORC, S02RC, -NRCRd, -NRCCORd, -NRCCO~Rd, -CO2RC or -CONRaRd;
- ~11 represents aryl selected from phenyl and naphthyl; heteroaryl selected from indazolyl, thienyl, furyl, pyridylj thiazolyl, tetrazolyl and quinolyl;
benzhydryl; or benzyl; wherein each aryl or heteroaryl moiety may be substituted by Cl_6alkyl, Cl_6alkoxy, halo or trifluoromethyl;

21 ~3Q7~ ~

-- 10 ~

Rl2 and Rl3 each independently represent ~, halo, Cl_6alkyl, oxo, CO2RC or CONR~Rd;
R14 represents Cl_4alkyl, optionally substituted by oxo, substituted by an optionally S substituted aromatic heterocycle; and R~ and Rd each independently represent H, Cl_~alkyl, phenyl optionally substituted by Cl_6alkyl or halo or trifluoromethyl.
Suitable values for the heterocyclic moiety of R14 include thienyl, furyl, pyrrolyl; pyridyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, pyrazinyl, pyridazinyl, oxazolyl, oxadiazolyl, thiadiazolyl, isoxazolyl, quinolyl, isothiazolyl, imidazolyl, benzimidaæolyl, benzoxazolyll benzothiophenyl, benzofuranyl and îndolyl.
In one sub-class of compounds of formula SIA), Rc and ~d each independently represent H, Cl_6alkyl, phenyl or tri~luoromethyl~
~ further subclass of compounds of formula (IA) is represented by compounds wherein n is 2 or 3; Rl2 and Rl3 each independently represent H, halo, C}_6alkyl, C02RC or C~NR~Rd; R14 represents Cl_4alkyl substituted by an optionally substituted 5- or 6-membered aromatic heterocycle; and Rc and Rd each independently represent ~, Cl_6alkyl, phenyl or tri~luoromethyl. For the 2S compounds of this subclass, suitable values for the heterocyclic moiety of Rl4 include thienyl, furyl, pyrrolyl, pyridyl, pyrazolyl, triazolyl, tetrazolyl, thia7.olyl, oxazolyl, oxadiazolyl, thiadiazolyl, ,-isoxazolyl, isothiazolyl and imidazolyl. t A preferred sub-class of compounds according to the i~vention is rspresented by compounds of ~ormula (IB), and salts and prodrugs thereof:

2 ~ 3 3 ~ ~ 7 j~"'L ~ 3'J~

~ 2 o ,~2~

~X
( CH2 ) Z~

~N/~R 2 - (1~) wherein X represents 0 or S, preferably 0;
Y is as defined for formula (I), preferably Cl_2alkyl optionally substituted by oxo, more preferably CH2 or CH(CH3);
R2 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;
R8 is as defined for formula (I); and R20 and R21 independently represent H, Cl_6alkyl, C2_6alkenyl, C2_6alkynyl, bromo, chloro, .fluoro, iodo, cyano~ nitro, trifluoromethyl, trimethylsilyl, ORa, SRa SORa, S02Ra, NRaRb, NRaCORb, NRaCO2Rb, CORa, C02Ra or CONRaRb, where Ra and Rb are as previously defined; and z is 1 or 2.
Particular values of R20 and R21 include H, methyl, t-butyl, methoxy, i-propoxy, chloro, fluoro, nitro, amino, methoxycarbonyl, carboxamido and triflu~romethyl. Preferably R20 and R~l are both other ..
. -- , - --.. c~ ..

2 1 ~ 7 ,' WO93/21181 PCT/GB93~00788 ~ 12 -than H, more preferably Cl_6alkyl, 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 R8 is optionally substituted pyrrolyl, pyrazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, imidazolyl, benzimidazolyl, benzoxa~olyl, 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, - benzimidazoly}, 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 RB is optionally s~bstituted 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, howe~er, be useful in the preparation of the compounds accordin~ to the invention (such as the dibenzoyltartrate salts~ or of their pharmaceutically acceptable salts. Suitable pharmaceutically acceptable salts of the compounds sf this invention include acid addition salts which may, for example, be formed by mixing a solution of the compound according to the in~ention 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 WO93/21181 2 1 3 ~ 0 7, PCT/CB93/00788 acid, phosphoric acid or p-toluenesulphonic acid. Salts of amine groups may also comprise guaternary 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 mekal 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 ~5 compositions co~prising one or more compounds of this invention in association with a pharmac~utically acceptable carrier. Preferably these compositions are in ~nit dosage forms such as tablets, pills, capsules, powders, granules, solutions or ~uspensions, 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 co~prising a compound of fon~ula (I)l or a salt or prodrug thereof, and a pharmaceutically acceptable carrier, which~process comprises bringing a compound of formula (I), or a ~alt 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, 2 ~ 3 v Q .
WO93/21181 PCT/GB93/00788' sucrose, sorbitol, talc, stesric acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceu~ical diluents, e~g. water, to form a solid preformulation composition containinq 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 subdiYided into equally ef~ecti~e unit dosage forms such as tablets, pill5 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 acti~e ingredient of the present invention. The tablets or pills of the novel composition Gan 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 2U component, the latter being in the form of an e~velope 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 intac~ into the duodenum or to be delayed in release. A
variety of materials can be used for such ~nteric 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 pre~ent invention may ~e incorporated f or administration orally or by injection include aqueous solutions, suitably fla~oured syrups, aqueous or oil suspensions, and flavoured emulsions with edible oils WO93/21181 ?1~ ~J?~0 7 l PCT/GB93/00788 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 S 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, a~ueous 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 î~ preferably sterile pharmaceutically acceptable solvents may be nebulised by~use of inert gases. Nebulised so~utions 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 ~he formulation in an appropriate mannar.
The compounds of~formula ~I) are of ~alue in the tre~tment of a wide variety of clinical conditions which are characterised by the presence of an excess of tachykinin, in particular substance P, acti~ity. 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 æclerosis (MS) and amyotropic lateral sclerosis (ALS; Lou Gehrig's disease) and other rJS 17 i ,", , WO93/21181 PCT/GB93/007X8' 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 suoh as inflammatory bowel disease, psoriasis, fibrositis, osteoarthritis and rheumatoid arthritis; allergies such as eczema and rhinitis;
hypersensitiYity disorders such as poison ivy; ophthalmic disea~es 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 ~houlder/hand syndrome;
dysthymic disorders; adverse immunological reactions such as rejection of transplanted tissues and disorders related to immune enhancement or suppression such a~
systemic lupus erythematosis; gastrointestinal (GI) disorders and diseases of the GI tract such as disorders associzted with the neuronal control of vi~cera such as ulcerative aolitis, Crohn's disease and incontinence;
emesis, including acute, delayed and anticipatory emssis, 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. ~or example, the compounds of`

21~30~7 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; respira~ory diseaæes, particularly those associated with excess mucus s~cretion, such as chronic obstructive airways disease, bronchopneumonia, chronic bronchitis, cystic fibrosis and asthma, and bro~chospasm; inflammatory diseases such as inflammatory bowel disea~e, 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 ~ontrol of viscera such as ulcer~tive colitis, C~ohn'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 o~ pain in migraine~
The compounds o~ formula (I) are particularly us~ful in the treatment of pain or nociception and/or inflammation and di~orders associated therewith such as, for example, neuropathy, such as diabetic and chemotherapy-induced neuropathyt postherpetic and other neuralgias, asthma, osteroarthritis, rhaumatoid arthritis and especially migraine.
Th~ present invention further provides a compound of formula (I) for use in therapy.
According to a further or alternatiYe aspect, the present invention provides a compound of formula (I9 for use in the manufacture of a medicament for the treatment of physiological disorders associated with an excess of tachykinins, especially substance P.

~ s 3~7 ~
WO93/21181 PCT/GB93/00788 !

The present invention also provides a me~hod for the treatment or prevention of physiological disorders associated with an excess of tachykinins, especially substance P, which method comprises S ad~inistra~ion to a patient in need thereof of a tachykinin reducing amount of a compound of for~ula (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 irl conjunction with another pharmacologically active agent . For example, f or the treatment of re~ipiratory diseasPs such as asthma, a compound of formula (I) may be used in conjunction with a bronchodilator, such a~ a ,B2-adrenergic receptor antagonist or tachy}cinin antagonist which acts at NK-2 receptors . The compound of f ormula ( I 3 and the bronchodilator may be administered to a patient simultaneously, sequentially or in c:ombination.
: ~ The present invention accordingly provides a 2 0 method f or the treatment of a respiratory disease, such as asthma, which method comprises administration to a pa~ient in need thereof of an effecti~e amount of a compound of formula (I) and an effective amount of a bronchodilator.
The present in~ention also provides a compssition 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 suita~le dosage level is about O.OOl to 50 mg/kg per day, in particular about O.Ol to about 2S mg/kg, such as from about 0.05 to about lO
mg/~g of a compound of formula (I) per day. For example, in the treatment of conditions invol~ing the 21 3~0 ' ~
WO93/211~1 PCT/G~93/00788 neurotransmission of pain sensations, a suitable dosage level is about O.OOl to 25 mg/kg per day, preferably about 0.005 to lO mg/kg per day, and especially about 0.005 to 5 mg/kg per day. The compounds may be S administered on a regimen of 1 to 4 times per day, preferably once or twice per day.
According to one general process (A3, the compounds according to the invention may be prepared by a process which comprises reacting a compound of fo~mula (II~:

R~ ~ X ~

R H

( I I ) wherein Rl, R2~ R4, R5, X and n are as defined for formula (I) above, with a reagent sui~able to introduce the group Y-R8, for examp}e, a halide or acyl halide, or corresponding mesylate or tosylate, of formula R8-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 R8 represents 5-oxadiazolyl may be J~ 7 l prepared by reaction of a compound of formula tIII) with a compound of formula (I~

R~
R~ X-- NOH

~> R2 ~2NJ~

O~O R 3 ( I I I ) ( lV) wherein Rl, R2, R4, R5, X, Y and n are ac defined for formula (I), R3~ represents an alkyl group and R3l represents H or a suitable substituent such as Cl_6alkyl, Cl_6alkoxy, halo, NRa ~ or NRaCORb, where Ra and Rb 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 solYents will be appropriate will depend on the nature of the base used.
For example, where the base usad is an alkali metal, suitable solvents will include alcohols, for example, ~ethanol, whereas where the base used is an alkali hydridej 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 R8 represents tetrazo~yl may be prepared from intermediates of formula (V):

~ 13~ ~, 7 ~

R
t:N

(V) wherein Rl, R2, R4, R5, X, Y and n are as defined for formula (I) by treatment with an alkali metal azide, such as sodium azide.
m e reaction is conveniently effected in a high ~; - 15 boiling organic sol~ent, such as, for example, :
N-methylpyrrolidinone.
According to a further process, (D), compounds of formula (I) wherein R~ represents thiazo~yl may be prepared from intermediates of formula (VI):
R~

; R

S~NH2 ~VI~

wherein Rl, R2, R4, R5, X, Y and n are as defined for ~ormula (I), by reaction with a compound of formula Hal-C~2C(O)-R60, where Hal represents halo, such as bromo, chloro or iodo, and R60 represents H or a suitable substituent such as Cl_6alkyl.

2 1 ~
WO93t21181 PCT/GB93/00788 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, S such as the reflux temperature of the chosen solvent.
According to a futher process, (E), compounds of formula ~I) wherein R~ represents thioxotriazolyl may be prepared from intermediates of formula (VII) Rl X~

( C\~ R 2 R 5~

O~NHNH2 (~1 1) wherein Rl ~ R2 ~ R4 ~ R5 r X ~ Y and n are as defined for formula (I), by reaction with a compound of formula R61NCS,- wherein R61 represents H or a suitable substituent such as Cl_6al~yl, in the presence of a base.
Suitable bases of use in the reaction include orga~ic bases such as, for example, 1,8-diazabicyclo~5.4.03undec-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 R8 represents unsubstituted or s~bstituted triaz~lyl may be prepar~d by reaction of intermediates of formula (II) with a compound of formula (VIII):
3 3 7 ~ ~

,~

R1~ NHN ~r~

t ~ I I I ) wherein Y and Hal are as previously defined and Rl8 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 ~etal carbonates, such as, for example, potassium carbonate.
Suitably Rl8 represents H, OCH3 (which is converted to an oxo substituent under the reaction conditions) or CONH2.
The reaction is con~eniently effected in an anhydrous organic solvent, such as, for example, anhydrous dim~thylformamide, preferably at elevated temperature, such as about l40-C.
- According to a further process, ~G), compounds of formula (I) wherein R8 represents s~bstituted or unsub~tituted 1,3,5-triazine may be prepared by reaction 2S o~ inter~ediates of ~ormula (~X):

2 ~ 3 3 .~ 7 ~

(C ~ 2 R
R~ r - HN~NH2 ~ I X ) wherein Rl, R2, ~4, R5, X, Y and n are as defined for formula ( T ~, with substitu~ed or unsubstituted 1,3,5-triazine.
The reaction is con~eniently effected in a 15: suitable organic solvent, such as acetronitrile, at levated temperature, such as 80-90'C, preferably about 82~C.
According to a fur~her process, (H), compounds of formula (I) wherein R8 represents substituted or unsubstituted 1,2,5-triazine may be prepared by reaction o~ an intermediate of ~ormula ~X) with a dicarbonyl : compound of ~ormula (X~):
k 1 HN~NHNH2 (X) (XI) WO93/~1181 ~ 3 0 7 I PCT/GB93/007~8 wherein Rl, R2, R4, R5, X, Y and n are as defined for formula (I) and R35 and R36 each independently represnt H
or a suitable substituent such as Cl_6alkyl, e~g. methyl.
The reaction is co~veniently 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. ~ed. Chem, ~, (1984), 849.
Compounds of formula (I) may also be prepared from other co~pounds of formula (I) using suitable interconversion procedures. For example~ compounds of ~ormula (I) wherein Y r~presents Cl_4alkyl substituted by an aromatic heterocycle may be prepared from compounds of formula ~I) wherein Y represents Cl_4alkyl substituted by oxo by reductio~, for example, using borane. Suitable interconversion procedures are de~cribed in the accompanying Examples, or will be readily apparent to those skillPd in the art.
Intermediates of formula (III) may be prepared from intermediates of formula ~II) by reaction with a compound of formula Hal-Y-C02R30, where Hal represents halo such as chloro, bromo or iodo and R30 and Y are as a~ove defined, in the presence of a base. Suitable bases include tertiary amines, ~or example, triethylamine.
Conveniently the reaction is effected in a suitable organic solvent, such as an ether, for example, tetrahydrofuran, at elevated temperatur~, such as the reflux temperature of ~he sol~ent.
Intermediates of formula (IY) are commercially available or may be prepared from commercially available ma~erials by conventional procedures well-known to those s~illed in the art.

2 ~ 3 ~

Intermediates of fo~mula (II) may be prepar~d as described in published European patent application no.
0 5~8 49S.
Intermediates of formula ~V) may be prepared from intermediates of fo~mula ~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 foFmula ~VI) may be prepared from intermediates of formula (V) by treatment with an alkylthioamide, such as, for example, thioacetamide.
Intermediates o~ ~onmula (VII) may be prepared from intermediates of formula ~III) by treatment with hydrazine. The reaction is conveniently ef~ected in a suitable organic so~vent~ suc~ as an alcohol, for example, ethanol, at elevated temperature.
Intermediates of formula tIX) may be prepared from intermediates of formula (II) by reaction with a compound of formula Hal-Y-C(NH)NH2, where Hal an~ Y are as previously definad.
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 ~or t-butoxycarbonyl, follnwed by deprotection under acidic conditions.
Compounds of form~la (XI) are commercially available or may be prepared from commercially available compounds by known methods.
Where th~ above-dèscribed prccess for the preparation of the compounds according to the invention gives ris~ to mixtures of stereoisomers these isomers may, if de5ired t be separated, suitably by conventional techniques such as preparative chromatography.

2 ~
WO93/211~1 PCTtGB93/0078 The novel compounds may be prepared in racemic form, or indivîdual enantiomers may be prepared either by enantiospecific synthesis or by resolution. For example, any suitable intermediates may be resol~ed 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 sequenc~s it may be necessary and/or desirable to protect sensi~ive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting group~, such as those described in Protective Groups_in Oraanic Çhemistrv, ed. J.F.W. McOmie, Plenum Press, 1973;
and T.W. Greene and P.G.N. Wuts, Protective Grou~s in Oraanic Svnthesis, John Wiley & Sons, 1991. The protecting groups may be removed at a convenient subsequ~nt stage using methods known from the art.
The following Examples illustrate the preparation of compounds according to the inventionO
-~ The substance P antagonising activity o~ the ~- compounds described herein was evaluated using the human NRlR assay described in published European patent application no. 0 528 495. The method essentially involves determining the con~entration of the test compound required to reduce by 50% the amount of radiolabelled subætance P binding to human NKlR, thereby affording an ICso value ~or the test compound~ The compounds of Examples l-lO~ for example, were found to ha~e ICso values less than 500nM.

3 3 7 ~,' WO 93/21181 PCI~/GB93/0078X

DESGRIP~IO~ ~ c~s-3-t(3.~-Bi~(trifluorQmethvl)l)henYl)met~l o~)-2-phenvliipelidin~ h~vdrochlQri~ialt - a) A solution of methyl 4-nitrobu~rate (23g3 aIld be~zaldehyde (16ml) in acetic acid (39ml) containing arnmonium 5 acetate (12.12g) was heated at reflu~ under nitrogen for 2h. The reactio~ ture was cooled to 5C, whereby a pale-yellow solid crystallised. This was isolated by filtration, then dissolved in dichloromethaIle, washed cautiouslv with saturated aqueous sodium bicarbonate solution (2 ~), then dried (MgSO4) and 10 concentrated to leave a yellow solid. Recrystallisation ii~om ethyl acetate provided 5-nitro-2-o~Q-6-~ lpiperidine (12.5g) as a crystallirle, white solid. lH NMR (CDCl~) d 7.46-7.26 (m), 6.0 (br s), 5.24 (ddJ J = 1.4, 7.0Hzj, 4.7G (m), 2.70-2.50 (m), 2.38-2.24 (m).
b) Potassium t-buto~ide (1.68g) was added to a solution of 5 nitro-2-oxo-6-phenylpiperidine (3g) in a mi~cture of dic~lorome~e (50ml) and methanol (50ml) and the ~re was cooled to -78C under s~itrogen. Ozorle was bubbled through the solution ~or 3h. A yellow-green solution resulted, and TIJC
20 indicated no starti~g mate~ial remained. The reaction ~re was purged with o~ygen for 5 min to remove excess ozone, then dimethylsulfide ~7ml) was added and the reaction mi~ e was allowed to warm to 23C. The solvent was removed in vacuo, and the re3idue was par~tioned between dic~loromethane and 25 water. ~he layers were separated, and the aqueous phase was e~tracted twice with dic~loromethane. The combined orgallic e~tracts were washed with brine, the~ dried (K2CO3) and concentrated to leave a yellow solid.
This c~de material was slurried in dry tetrahydrofi~ran 30 and added to lithium aluminiu~ hydride ~1M in THF, ~0ml) then heated at reflux for 12h. Afcer cooling to 23C, the reaction 213 ~, ~n 7r!
WO 93/21181 PCl'/GB93/00788 mi~ture was quenched by t he cautious addition of water~
(dropwise) under nitroge~, then 2M sodium hydro~nde. The mixture was filtered through a pad of Hyflo, the filtrate was washed ~nth brine, l;hen dried (K2CO3) and concentrated to 5 leave a yellow solid. Purification by silica-gel chromatography (CH2Cl2/MeOH/NH3 97:3:1 ~hen CH2Cl2/MeOH 9~:5) provided 3-hYdro~v- 2-~henvl~i~eridin~ as a ~ 4:1 mi~ture of ~ and ~r~ns-isomers respect*ely. lH NMR (CDCl~) 7.44-7.20 (m), 3.84 (23, 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, d = 2.9, 11.9, 11.9Hz), 2.18-1.78 (m), 1.48 (m). MS (EI) m/z 177 (M+).
c) Di-t-butyldicarbonate (1.36g) was added to a solution of 3-hydro~y-2-phenylpiperidine (lg) in dichloromethane (8ml~
under n~trogen and the mixture stirred at 23C for 3h. The solvent was removed in vacuo, and the residue purified by silica-gel chromatography (CH2Cl2JMeOH/NH3 97:3:0.5) to provide czs- and trans-l-t-butvlo~arbonYL~
~henvl~2cri~1i~ (1.4g) as a ~lear, viscous oil. lH NMR (CDCl3 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 (0C~ solution of 1~t-butylo~ycarbonyl-3 hydroxy-2-phenylpiperidine (1.4g) in dry dimethylformamide ~5ml) was added sodium hydride (8Q%~dispersion in mineral oil;
182mg). The cooling bath was removed and the reaction mi~ture stirred at 23C for 30 min. A solution of 3,5 bis(tri~uoromethyl)benzyl bromide (1.87g) in dry dimethylfonnamide (1ml) was added and stirT~g was continued for 2h at room temperature. The mi~ture was diluted with wa~er (100ml) and extracted with ethyl acetate (3 ~ 40ml). The - combined organic extracts were washed with brine (1 x 30ml), 2 t 33 ~7 l ~
WO 93/21181 PCl/GB93/00788 dried (Mg~04) and evaporated to yield a pale yellow oil:~
Purification by chromatography on silica USiIlg gradient elution of he~ane in ethyl acetate (9:1 - 4:1) affiorded the product czs-l-t-butvlox~ca~onvl-3-((3~-bi~(tri~uoromç~
5 meth~lo~n)-2-ph~~ (350mg) as an oil. lH NMR
(250MHz, CDCl3) d 7.77 (lH, s, ArH), 7.71 (2H, s, ArH), 7.53-7.57 (2H, m, ArH), 7.2-7.4 (3H, m, ArH), 5.70 (lH, br d, app. J = 7.0Hz, NC~Ph), 4.73 (2H, brs, OCH2), 3.84-3.98 (2H, rn, NCHC~O + NC~IH), 2.77 (lH, ddd, J = 13.û, 13.0, 3.0Hz), NC~), 2.0012H, mc, CH2), 1.6-1.8 (2H, m, CH2), 1.40 (gH, s, C(CH3)3).
e) Tri~uoroacetic acid (3ml) was added to the product of (d) above (800mg) under nitrogen and the resulting solution was stirred for lh. E~cess trifluoroacetic acid was removed in vacuo 15 and the residue was p~tioned be~veen 2M sodium hy~ro~ide and dichloromethane. The org~c phase was washed with - bIine, dried (MgSO4) aIld evaporated to af~ord a colourless oil.
Purification on silica (dichloromethane in methanol, 98:2 - 9~:5) afforded the product ~is-3-((3,5-bis(trifluoromethyl)phenyl) 20 methylo~y-2-phenylpipendine (36ûmg) as a colourless oil. lH
NMR (360~z, CDCl3) d 7.78 (lH, s, ArH)~ 7.44 (2H, s, ArH), 7.18-7.3& (5H, 8, ArH), 4.52 (lH, d, J = 12.5Hz, OC~I), 4.13 (lH, d, J = 12.5Hz, OCH~), 3.84 (lH, d, J _ l.OHz, NCHPh), 3.68 (lH, d, J = 1.5Hz), 3.28 (lH, m, NCHC~O), 2.84 (lH, ddd, 2~ J _ 3.0, 12.5,12.5Hz, NcEH)~ 2.20 (lH, mc, NCH~, 1.8-1.98 (2H, m, CH2), 1.64-1.78 (lH, m, C~I), 1.50~ 8 (lH, m, CH~);
MS m/z 404 ((M+1)+, 90%).
The oil was dissolved in e~er to which was added e~cess ethereal hydrogen chloride. Upon standing a w~ite ~olid 30 crystallised. This was filtered and re~stallised ~om ethyl acetate~methanol to afford the title compo~nd as white cry8tals:

- 2 ~ 3 t, 0 7 1 WO 93/21181 PCl/GB93/00788 mp 200-203C. lH NMR (360MHz, DMSO) d 7.95 (lH, s, ArH), 7.81 (2H, s, ArH), 7.37-7.47 (5H, m, ArH), 4.78 (lH, d, J =
13.0Hz, O~EI), 4.56 (lH, s, NC~Ph), 4.32 (lH, d, J = 13.0Hz, OCH~), 3.96 (lH, s, NCHCHO~, 3.10 (lH, t, J = 13.0Hz, NC~H), 2.23 (lH, d, J = 13.0Hz, NCH~), 1.64-2.00 (4H, m, CH2 2); MS (CI+) m/z 404 ((M+1)+, 90%); Found: C, ~4.08; H, 4.47;
N, 3.13. Calcd. for C2oH2oF6Nocl.o.25H2o C, 54.06; H, 4.65; N, 3.15~o.

DESCRIPTIQN 2: (2R*,~.-((3.5-;~is~trifluoromç~hvl)~henv~) methvlo~v)-l-(carbomc~hQ~z~vl-2-Dhenylpi~elidi~
cis-3-((3,5-Bis(trifluoromethyl)phenyl)methylo~y)-2-pheny lpiperidine hydrochloride (Descrip~on 1, lg) was liberated fi om the hydrochloride salt by partitioning between ethyl acetate aIld 1~ 2M sodium hydro~ide. The organic phase wa~ washed successively wi~h water, saturated brine, dried (MgSO4) aIId 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 reflu~ under an atmosphere of nitrogen for 16h. To the cooled solution was added ethyl acetate and water and the organic phase washed filrther wit~ water and drîed (MgSO4). Afl;er the solvent had been removed in vacuo ~e residue was chromatographed on silica gel eluting with et;hyl acetateJpetroleum ether (3:103. The product was recrystallised from die~hyl ether/petroleum ether to give the ~itle comso~
mp 81-83C. Found: C, ~7.35; H, 4.98; N, 2.84 C23H23F6NO3Ø1(H2O) requires C, 57.71; H, 4.86; N, 2.93%. MS
(CI+) m/z 476 (M+H)+.

2 ~ J 7 ~
wo 93~21181 Pcr/Gsg3/oo7gx DESCRIPTI~2N _3: (+~-(2i.3S)-cis-3-((3.5-Bis(tri~Qromethvl) phenvl)met~lylo~v)-2- ~henvl~ eridine hvdrochloride sal~
a) The mi~ture of cis- and trans-isomers of 3-hydro~y-2-phenylpiperidine (Description 1, (~b)) and 4-toluenesulfonic acid monohydrate was crystallized from meth~noVethyl acetate to give cis-3-hydroxy-2-phenylpiperidinium tosylate: ~p 266-267C.
b) The to~la~al~ (Description 3(a) above) was dissolYed in a miYture of ethyl acetate and 10% aqueous Na2CO3 with warming. The organic phase was washed with saturated brine, dned (K2C03) ~d evaporated to give crystalline cis-3-hvdro~v-2-~henYl~ ~, mp 110-110.~C.
c) cis-3-Hydro~y-2-phenvlpiperidine (Description 3b) and (-)dibenzoylt~ate were dissolved in methanol and crgstallized by addition of ethyl acetate. The solid was recrystallised fi~om hot methanol to~ giYe the hemi dibenzovl~rt~ salt: mp 223-224G. This was liberated ~om the salt as described aboYe to give the single enantiomer (+~-cis 3-hydro~y-2-phenylpiperidine, mp 93-95C. [a~23D = +98.5 (c~1, MeOH).
The mother liquors were converted to the fi~ee base as described in De~sc~ption 3b and crystallization using (+)dibenzoyltar~ate in an analogous m~nner to that described above gave f:~3-hvdr~-2-~h~nvl~ipçndine, mp 93-95C. [aJ23D = -97.2 (c=1, MeOH~. .
d~: (+~cis-3^Hydro~y-2-phenylpiperidine was reacted according to the procedure detailed in Descrip~on lc-e to give (+)-cis-3-((3,5-bis(tri~uoromethyl)phenyl)met;tlyloxy-2-phenylpiperidine hydrochloride as a cr~stalline solid: mp 215-216C. [a]D = +87.~ Ic=l, MeOH). lH NMR (360MHz, DMSO-d6) d 7.95 (lH, s, ArH), 7.81 (lH, s, ArH), 7.47 (2H, m, ArH), 7.37 (3H, m, ArH), 4.78 (lH, d, J = 13.0Hz, OC~H), 4.56 ?. ~ 3 ~ n 7~l WO 93/21181 PCr/GB93/00788 (lH, s, NC~Ph), 4.32 (lH, d, J = 13.0Hz, OCH~), 3.96 (lH, s, NCHCEO), 3.10 (lE, t, J = 13.0Hz, NCEH), 2.23 (lH, d, J =
13.0Hz, NCH~), 2.00-1.64 (4H, m, CH2 x 2); MS lCI+) m/z 404 (M+1+, 90%); Found: C, 54.~2; H, 4.60; N, 3.11. Calcd. for C20HlgF6NO~HCl C~ 54.62; H, 4.58; N, 3.18%.

DE~CRIPTION 4: 1~)-(2~)-3-((3 5-Bis(~i~aQ~omiethvl~
ghenvl~meth~ZlQx~r)-1 -(carbomçthQ2~)rrleth~l-2-~h~pvl~il2eridiIle The ~le com~ound wa~ prepared firom (~)-cis-3-((3,5-bis (trifluoromethyl)phenyl)methylo~cy)-2-phenylpiperidin~
(Description 3) usi}lg ~e procedure detailed in Description 2:
mp 60-7ûC. ~a]D = +132.3 (c=1, MeOH). lH NMR (360MHz, CDCl3) d 1.57-1.63 (3H, m, CH2 + CHH), 2.04-2.17 (2H, m, C~I, CEHN), 3.07-3.10 (lH, m, NCHCEO), 3.20 (lH, d, J =
l~i 17.0Hz, NCH~CO2CH3), 3.31 (lH, d, J = 17.0Hz, NC~EI
CO2CH3), 3.58 ~3H, s, CH~), 3.93 (lH, s, NCEPh), 4.07 (lH, d, J
= 12.0Hz, OC~), 4.49 (lH3 d, J = 12.0Hz, OCH~), 7.28-7.34 (3H, m, ~I), 7.43-7.4~ (2H, m, ArH), 7.54 (2H, st ArH), 7.71 ~lH, s, ArH). MS (CI+) m/z 476 (M+1+, 100%). Found: C, 58.31;
~ H, 4.90; N, 2.94. Calcd. for C2~H~3F6NO3: 58.11; H, 4.88; N, 2.9~%.

DESCRIPI IQN 5: (2R*.3R*)-3-((3~-~i~trifluom~l~?he~l~
methvlo~)-l-(cYanom~th~,Tl)-2-phen~ eridinium ,.
~lY~hlQ~
The compou~d of Des~ption 1 (5g), potassium carbonate (1.7g) and bromoacetonitrile (0.87ml) were suspended in dimet~ylfo~amide (1~ml) and the mi~ture was stirred under nitrogen at 60C for 3 h. The ~e was cooled, diluted with water (200ml) and e2tracted with ethyl acetate (2 x 50ml). The organic extracts were wa~hed with bnne, dried (MgSO4) and 2 1 ~ 7 r~
WO 93/21181 PCI`/G~B93/00788 `

evaporated, af~ordîng a browll oil. This was purified on sîlîca using ethyl acetate in petrol (105b) as elua~t. Thîs afforded the product as a colourles~ oil. The hydrochloride salt was prepared by dîssolutîon in ethereal hydrogen chloride and th~ salt was recrystallî6~d firom e~er-hexane: mp 133-134C. lH NMR
(360MHz, CDCl3) d 1.75 (2H, mc, C~)9 1.90 (2H, mc, CH~), 2.31 (lH, mc, C~l), 2.71 (lH, mc, CH~), 3.19 (lH, mc, CH~
3.72 (lH, mc, C~ , 3.81 (lH, d, J = 17.5Hz, NC~ICN), 3.86 (lH, s, CHO), 4.02 (lH, d, J = 17.5Hz, NCH~CN), 4.09 (lH, s, C~h), 4.3~ (lH, d, J = 13.0Hz, OC~H), 4.73 (lH, d, J =
13.0Hz, OCH~), 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 CæHl8F6N2O~HCl: C~ 55~l8; H, 4~42; N, 5~85~o~

DESGRIPTION. 6: (2R*.3R*)-3~.5-Bis(tri~aQrom~tl~ henyl) mcthvlo~v)-2-Dhenyl-l-(thiQc~rbo~a~ smet~~ eridi~e The compound of Descnption 5 (lg) was dissolved in dimethylformamide (anhydrous, 10ml) and ~e solution was sat~ated with dry hydrogen chlonde gas. The reaction was heated to 100C Imder nit~ogen and thioacetamide (0.34g) was added; thi8 mi~tur0 was allowed to sl;ir at 100G for 3h.
I)imethy~o~de was removed in vacuo~ The resîdue ~as extracted with ethyl acetate and the organic layer was washed ~nth aqueous sodium bicarbonate, brine, dried (MgSO4) and concent~ated in vacuo to af~ord a brown oil. Tbis was purified on silica using a gradient elution of ethyl acetate in petrol (10-50%). The product was filrther purified by re~ystallisation firom ethyl acetate-pet~ol: mp 164-166C; lH NMR t360M~Iz, CDCl3) d 1.56-1.70 (2H, m, CH2), 1.96-2.10 (lH, m, C~I), 2.15-2.32 (2H, m, CEHN + CHH), 2.98-3.06 (lH, bd, NCH~), 3.09 (lH, d, J = 18.0Hz, C;~HSNH2), 3.50 (lH, d, J - 18.0Hz, 2 1 ~? ~3 ()7 1 NCH~CSNH2), 3.~0 (lH, s, C~O), 3.60 (lH, s, NC~Ph), 4.04 (lH, d, J = 12.0Hz, OCEHAr), 4.47 (lH, d, J = 12.0Hz, C~C~IAr), 7.26-7.36 (5H, m, CH~), 7.63 (2H, s, Ar-H), 7.75 (H, s, Ar-H), 7.61 (lH, bs, N~I), 8.99 (lH, bs, NH~); MS (CI~) m/z 477 (M++l, 1~%); FolLnd: C, ~6.09; H, 4.58; N, 5.97. Calc for C22HæF6N2OS: C, 55.46; H, 4.65; N, 6.88.

DE~ ION 7~ (2~*~R*)-3-~3~ 3is(trifluQronlethvl)l~henyl~
methvlo~r2~1-(ca~o~hydrazidQme~hYI)-2-phenvlpi~eridinium ~
Hydrazine hydrate (3.0ml) was added to a solution of the compound of Description 2 (2.~5g) in ethanol (80ml). The solu~on was hea~ed at reflu~ for 18h a~er which the ethanol was removed in vacuo. The residue was e~tracted into ethyl acetate and th2 org~c layer was washed with brine, dried (MgSO4) a~d conce~trated to give the title compound (2.79g).
This was dissolved in methan~l (5ml) and a methanolic solution of hydrogen chloride was added. Methanol was removed in vacuo and the salt was recrystallised f~orn diethyl ether to give 2û 'che hydrochloride salt. lH N~ (360MHz, DMSO) d 1.77-1.93 (2H, m, CH2), 2.08-2.21 (lH, m, CH2), 2.22-2.35 (lH, m, CH2), 3.56 (lH, d, NC~EICH2), 3.64 (lH, d, J = 16.5Hz, NC~HCO), 3.77 (lH, d, NCH~CH2), 3.92 (lH, d, J = 16.5Hz, NCH~CO), 3.96 (lH, brs, ~O), 4.37 (lH, d, J = 13.0Hz, OC~I), 4.83 (lH, d, J = 13.0Hz, OCHH), 4.96 (lH, s, CHPh), 7.36-7.46 (3H, m, ArH), 7.53-7.62 (2H, brs, ArH), 7.96 (2H, s, ArH), 7.97 (lH, s, ArH); MS (CI)+ m/z 475.

~;.~;CRIPTION 8: (2S.3~iL~is~laQrometh~l~e~
methvlQx~ ~o~azidQmethvlL~-~2henvlPiperidinium h~Q~Q~

2~ 3~a7~l WO 93/21181 PCrJGB93/00788 T~e title compound was prepared according to the~
procedure outlined in Descript;ion 7 using the compound of Descrip~on 4 as a starting matenal. lH NMR (360MHz, DMS0) d 1.77-1.93 (2H, m, CH2), 2.08-2.21 (lH, m, CH2), 2.22-2.35 (lH, m, CH2), 3.56 (lH, d, NC;~EHCH2), 3.64 (lH, d, J = 16.6Hz, NCHHC0), 3.77 ~lH, d, NCH~CH2), 3.92 (lH, d, J = 16.5Hz, NCH~C0), 3.96 (lH, brs, C~03, 4.37 (lH, d, J - 13.0Hz, OCEH), 4.83 (lH, d, J = 13.0Hz, OCH~), 4.95 (lH, s, CHPh), 7.36-7.46 (3H, m, ArH), 7.~3-7.62 (2H, brs, ArH), 7.95 (2H, s, ArH), 7.97 (lH, s, ArH); MS ((~I)+ m/z 475.

DESCRIPTI0~ 9: ~3~1-3-((3.5-~is(~rifluoromethvl)~h~nvl) methv!o~v)-1- (cvanomethvl)-2-phen~rlpiI!eridi~
~e title compound was prepared f~om the reaction of bromoacetonitrile and ~he compound of Description 3 according to the procedure detailed in Description 5. Purification by chromatography on silica using 10% he~ane in ethyl acetate afforded the product as a colourless oil. lH NMR (360MHz, CDCl3) d 1.75 (2H, mc, C~I2CH2N), 2.14 (2H, mc, CH2C~I2N), 2.63-2.74 (1H, m, C~HN), 2.96-3.06 (lH, m, CH~), 3.35 (lH, :: : d, J=17.0Ez, CE~ICN3, 3.48 (lH, d, J=2.0Hz, CHO), 3.55 (lH, d, J=17.0Hz, CHEN), 3.64 (lH, d, J=2.0Hz, C~Ph), 4.07 (lH, d, J=12.0Hz, OC~EI), 4.52 ~1H, d, J=12.0Hz, QCH~), 7.28-7.38 (3H, m, ArH), 7.4-7.48 (2H, m, ArH), 7.56 (2H, m ArH), 7.73 (lH, m, ArH).

DE~C~IPTION 10: (2S~3S)-3-((3-t-Butvl-5 methYlDhenvl) methYlo~ -2-phenvlni~c~in~
This compound was prepared from the compou~d of Descnption 3c and 3-t-butyl-5-methylbenzyl bromide, following the procedure desc~ibed in Descriptions lc-e. mp 180-182C. MS

WO 93/21181 2 1 ?~ 3 ~ 7 ï PCI /GB93/00788 (CI+) m/z 338 (M~1, 100%)~ FouIld: C, 73.81; H, 8.63; N, 3.74,~
Calcd. ~or C23H3lNO.HCl: C, 73.87; H, 8.62, N, 3.75%.

pESC~ IO~ 11: ~ -3-((~.5-Di~h.l~Q~henyl~methyl 5 2-phenvlni~:id~
This oompou~d was prepared ~om the compound of Descrip~on 3c and 3,5-dichlorobc~zyl chloride, ~ollowing ~he procedure described in Des~ip~ons lc-e. 'H NMR (CDCl3) 1.49-1.53 ~lH, m, C~I), 1.60-1.70 (lH, m, CHH), 1.82-1.95 (lH, m, C~IH), 2.14-2.18 (lH, m, CHH~, 2.79-2.87 l1H, m9 NCHH), 3~27-3.31 ~lH, m, NCHH), 3.60 (lH, s, CHO), 3.82 (lH, s, CHPO, 4.02-4.05 (lH, d, J=13Hz, OCHH), 4.31-4.35 (lH, d, J=13Hz, OCXEI), 6.80 (2H, s, ArH), 7.15 (lH, S9 ArH)~ 7.25-7.35 (5H, m, ArH). Found: C, 58.24; H, 5.38; N, 3.91. Calcd. for 1~ C~ 9Cl2NO.HCl: C, 58.01; H, 6.41; N, 3.76%.

meth~lo~D~e This compound was prepared from the compound of Desc2iption 3c and 3-chloro-5-methylbenzyl bromide, followi~g the procedure described in Dess:riptions lc-e: mp 235-237C. MS
(CI+) m/z 316 (M+~H, 100~o). Found: C, 64.68; H, 6.50; N, 3.98.
Calcd. for ClgH~2ClNO.HCl: C, 6~.~8; H, 6.58; N, 3.98~o.

~_ ~ _ ~ _ ~enylalanal A solution of methyl sulfo~ide (4.4ml) in dichloromethane (13ml) was added dropwise to a cooled (-78C) solution of oxalyl chlonde (4ml) in dicbloromethane (50ml). After 15 mi~, a solution of N-t-butylo~ycarbonyl-(S)-diphenylalanol (lOg) in 21~

dichloromethane (150ml) was added dropwise at -30C. The solution was allowed to stir for 3û min, triethylamine (17ml) was added and the solution was allowed to warm to -10C. Ice-water (200ml) was added to the solution which was then poured 5 onto he~:ane ~600ml). The organic phase was separated, washed success*ely wil~ citric a~d (200ml), saturated aqueous sodium bicarbonate t2 ~150ml), b~ine (1~150ml) then dried (MgSO4) and concentrated in vacuo to leave a white crystalline solid. lH
~ (250MHz, CDCl3) ~ 1.42 ~9H, s, C(CH3)3), 4.48 (lH, d),
4.86 (lH, d), 5.10 (lH, t), 7.26 (lOH, m, ArH), 9.6 (lH, s, CHO)o (b) N-t-But~lo~vc~Qnyl~ dinhenvlm~thyl)-~-hvdrQ~y-ent-4-e~u~-1-amin~
A solution of N-t-butyloxycarbonyl-(S~-diphenylal~al - (10.9g~ in tetrahydrofilran (60ml) was added dropwise to a 15 soluto~ of ally~ magnesium chloride (2M in tetrahydrofi~ran, 36ml) at -10C. After 30 min the mixture was poured onto ice-cold saturated aqueous ammonium chloride aIld the result~g mi~ture was e~tracted with etbyl acetate (3 ~ 150ml~. The combLIled organic e~tracts were washed ~nth brine (1~ lOOml), 20 1~en dried (MgSO4~ and concentrated irl vac~o. The residue was p~ed by c~hromatography on silica gel using hexane in ethyl acetate (gradient elution of 9:1 to 4:1) as eluant to affiord the compourld as a white solid. lH NMR (360MHz, CDCl3) ~ 1.42 (9H, s, (CH3)3), 2.22 (2H, m), 2.68 (3H, brs), 3.48 (t), 3.57 (lH, m), 3.86 (lH, s), 4.07 (d, J = llHz~, 5.04 (lH, m), 5.71 (lH, m), 6.97-7.36 (lOH, m, ArH).
(c) 2-((3.5-Bis(~uoromethvl)~henvl)methvln~l~-t-buh~lo~vcarbon~l-l-(di~henvlmethvl)-Dent-4-envl-1-amine Soditlm hydride (80% in oil, 0.53g) was added to a 30 solu~on of 3,5-bis(t~uoromethyl)benzyl bromide (5ml~ and t~e compound of (13b) above (6g) in dimethylfo~mamide (8ml). A~er 3 ~ (17 rl WO 93/21181 PC-r/GB93/007~8 stirring for lh water ~80ml) was added and the mi~ture was~
e~tracted with ethyl acetate (3 x 100ml). The com~ined organics e~tracts were washed with brine (1 ~ 100ml) then dried (MgSO"~) and concentrated to lea~e an oil which was purified on silica 6 using he~ane in ethyl acetate as eluant (gradient elution of 97:3 to 4:1). This afforded the title compound as a colourless oil. lH
NMR (360MHz, CDCl~) ~ 1.25 (s), 1.30 (s), 2.35 (m3, 3.31 (m), 3.40 (dd, J = 6.2, 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), 7.36-7.13 ~m), 7.76 (s), 7.86 (s3.
(d) (2S.~0-3-((~.5-Bi~ifluorom~hvl~h~l) meth~Q~Y-.2-(di~hen~lmethv!)~vrrnlidiDium hydrochlo~i~e A solution of the compound of (c) above (5.2g) in dichloromethane (40ml) and methanol (40ml) was treated with a stream of ozone in o~ygen at -78C for lh. Methyl sulfide (3ml) 15 was added and the mi~ture was wa~med to 23C and concentrated in vacuo. The residue was dissolved in chloroform (50ml), triçthylsila~e (5.6ml) was added followed by dropwise addition of a solution of b~ifluoroacetic acid (6.9ml) in chlorofo~n (~ml). After lh the solvent was e~aporated in vacuo a:nd 20 t;rifluoroacetic acid (10ml) was added to the residue. Aflcer sti~ng for 30 min the mi~cture was concentrated in vac~o and the residue wa6 par~tioned between dichloromethane and saturated aqueous sodium bicarbon~te. The organic layer was dried (K2C03) and co~centrated to leave a brown oil. This was 25 purified on 8ilica gel eluting with dichlorom~thane/methanol (99:1) to pronde the title compound as the ~ee base. Thi8 was converted to the salt by treatment with methanolic hydrogen chlonde: mp >230C. [a]23D = ~46.6 (c=1, CH30H). Found: C, 59.95; H, 4.74; N, 2.63%. Calcd. for C26H23F6NO.HClØ2H~O: C, 60.11; H, 4.73; N, 2.70~.

2~ 33~ ~
WO 93/21181 P~/GB93/00788 PESCRIPTION 14: t~3-((3.5-~is(t~ifluornmethvl~henY
methvlo~n)-2-(di~hen~l~b~~ u~ hYdrochloride The title compound was prepared ~om N-t-butylo~ycarbonyl-(R)-diphenylalanol by a procedure analagous 6 to that described in Description 13: mp > 230C. [a]23D = +12.1 (c=1, CH3OH).

DESCRIPTIQN 15: (2S.3S)~ 6-Dichlorophenvl)meth~lo~
2-(di~henvl met~l)p~rrolidiniun:l hv~roçhln~ide (a) N-~-Butvlo~vcarbonvl-2-((3.~-dis hl~rophenYll methvlo~v-l-(di~henYlmethvl~2çnt4-envl:l-~mirle The compound of Description 13b was alkylated with 3,6-dichloroberlzyl chloride by a procedure analagous to that described in Descrip1ion 13c, to af~ord the ti~e compound a~ a~
~ lH NMR (360MHz, CDCl3) ~1.25 (9H, s), 2.41-2.27 (2H, m), 3.32 (lH, m), 4.07 (lH, d, J-llHz), 4.13 (lH, d, J=12Hz), 4.30 (lH, d, J=12Hz), 4.66 (2H, m), 5.13 (2H, m), 5.76 (lH, m), 7.3~-6.60 (13H, m). MS (CI+) mlz 526, 528 (M~+1, 100%, 80%).
(bl t2S.3S)-3-((3.~i~hl~rQ~henvl)methvlo~)-2-(di~henvlmethvl)l~vrrolidinillm hvdrochloridç
The compound of Description 15a above wa~ treated with ozone followed by triethylsilane-trifluoroacetic acid by a procedure a~alagous to that described in Description 13d to a~ord the ti~e compound as a white crysta}line solid: mp>230 C. Found: C, 64.~2; H, 5.34; N, 3.12. Calcd. for C24H23Cl2NO.HCl: C, 64.23; H, 5.39; N, 3.12~.

pESCRl~N 16:_ (2S.3S)-3-((3-t-Butvl-5-chlQrQ~henvl) ~thvlo~v)~ h~vlo~gride ~a) _ 4-~-Butvl~ hloro-6-(m~thvlthio~neth~l)aniline 2 ~ 33a7~Y

4-t-Butyl-2-chloroar~line (30g) was dissolved in dic~loromethane (1.21) and the solution wa~ cooled to -~C. N-chlorosuccinimide (21.7g) was added portionwise to the vigorously s~red solution and stirring was continued for lh.
5 Dimethyl sul~de (35ml) was added to t~e solu~on (-5C) and stirring was continued for a filrther lh. The solution was then cooled to -65C and triethylamine (27ml) was added. This solut;ion was allowed to warm to room temperature overnight.
The solution was evaporated to half vollLme, wash d with 10 sodium hydro~de (lN), water and brine successively. The organic so!ution was dried and evaporated and the re~idue was purified on silica using he~ane to 3% ether in hexane as elu~t.
This af~orded the product (31.2g) as a red oil. lH ~MR (CDCl3, 250MHz) ~1.27 (9H, s, (CH3)3), 1.99 (3H, s, SC~3~, 3.69 (2H, s, C~I2SCH3), 4.38 (2H, br s, NH2), 6.92 (lH, d, J=2.0Hz, ArH), 7.21 (lH, d, J=2.0Hz, ArH). MS (CI ~ ) m/z 244 (M++1, 100%).
ÇbL~l~h1, ~bloro-6-~hv!aI~iline 4-t-Butyl-2-chloro-6-(methylthiomet~yl)aniline (1.3g) was dissolved in metharlol (50ml) and Raney nickel (prewashed to pH 7) was added portionwise until t.l.c. indicated all star~ng mate~ial had reacted (ether-he~ane, 1:10). The Raney nickel was removed by filtr~tion through celite and the filtrate was evaporated. The residue was dissolved in ether and washed with brine, dried (MgSO4) and e~raporated. The residue was purified 2~ on silica using he~ane - 5% ether in hexane as eluant to af~ord the product as a yellow liquid. lH NMR ~360MHz, CDCl3) ~ 1.26 (9H, s, (CH3)3), 2.19 (3H, s, CH3), 3.97 (2H, s, NH2), 6.97 (lH, d, J=2.0Hz, ArH), 7.14 (lH, d, J=2.0Hz, ArH).
(c~ 3-t-Butv1-5-chlo~
4-t-Butyl-2-chloro-6-methylaniline (1.97g) was dissolved in ethanol (50ml); sulphllric acid (1.88ml, conc.) was added 2 1 3 3 ~ 7 r) ~ ~

dropwise and the resulting blue solution was heated at reflu~.
Sodi~lm nitIite (1.72g) was added portionwise over 30 min. The resulting mi~ture was heated at reflu~ for a further 30 min, then cooled and was poured onto ice-water and extracted with 5 ether (2 x 50ml~. The ethereal extract was dried (MgSO4) and evaporated and the residue was purified on silica gel using he2~ane as eluant. This af~orded the product as a colourless oil.
lH NMR (360MHz, CDCl3) o 1.29 (9H, s, (CH3)3), 2.31 (3H, s, CX3), 6.98 (lH, brs, ArH), 7.05 (lH, brs, ArH), 7.1~ (lH, brs, ArH~. MS (CI~) mfz 181 (M+-H, 100~o).
(d) 3-~-Butvl-~-chlo~obenzv~ bromide 3-t-Butyl-~-chlorotoluene (5.7g) was dissolved in carbon tetrachloride (80ml) and N-bromosucciI~imide (5.56g) was added followed by beIlzoyl pero~de (750mg). This mi~ture ~vas heated 15 at reflu~ for 6h. The mi2~ture was cooled, filtered through celite and the filtrate was concentrated in uacuo. The residue was purified by chromatography on silica using hexa~e as eluant.
This afforded the l;itle compound as a colourless liquid. lH N~R
(360MHz, CDCl3) ~1.31 ~9H, s, (CH3)3), 4.42 (2H, s, CH2), 7.20 - 20 (lH, t, J=l.~Hz, ArH), 7.26 (lH, t, J=1.5Hz, ArH), 7.28 (lH, t, J=l.~Hz, ArH).
(e) f2S.3S)-I-t-Bul2lox~rcarbonvl-3-((3-t-butvl-5-chLoro-~envl)~hvlo~ 2-gh~nvl~i~eridin~
(+kis-3-Hydro~y-2-phenylpiperidine (Dest:rip~on 3c) was reacted wit~ 3-t-butyl-5-chlorobenzyl bromide (Description 15d above) according to the procedure detailed in Descrip~on lc-d to afford the t;itle compouIld. lH NMR (360MHz, CDCl3) ~ 1.27 (9H, s, C(CH3)3), 1.46 (9H, s, C(CHS)3), 1.~2-1.66 (2H, m), 1.8-2.0 (2H, m), 2.69 (lH, td, J=3.5Hz, 13.0Hz, NC~IH), 3.81 tlH, q, J=5Hz, NC~D, 3.92 (lH, brd, C~IO), 4.60 (2H, q, J=12H~, OCH2), 5.70 (lH, brs, CHPh), 7.10 (lH, s, ArH), 7.18 (lH, s, 2 ~ 3 .~ O . I
wo 93/21181 pcr/GB93/oo788 ArH), 7.22 (2H, s, ArH), 7.43-7.47 (2H~ m, ArH), 7.57-7.59 (2H,~
m, ArH).
(f) The compolmd of Description 15e abo~re was dissolved in methanolic hydrogen chloride overnight. The solution was 5 'Lhen co~centrated in vacuo and the residue triturated with ether. This af~orded the title compound as a white crystalline powder: mp 210-211C. lH NMR (360MHz, DM~O-d6) ~ 1.21 (9H, s, C(CH3)3), 1.66-1.8û (2H, m, CH2), 1.86-1.93 (lH, m, G~I), 2.18-2.22 (lH, m, CH~), 3.04-3.11 (lH, m, NC~I), 3.3 (lH, m, NCH~), 3.88 (lH, brs, CHO), 4.14 (lH, d, J=12E[z, OC~H), 4.52 (lH, s, CHPh), 4.53 (1H, d, J-12Hz, OCH~), 6.95 (lH, s, ArH), 7.00 (lH, s, ArH~, 7.24 (lH, t, J=1.8Hz, ArH), 7.3-7.~ (5H, m, ArH), MS (CI+) m/z 358 (M~+1, 100%). FouIld~
66.68; H, 7.29; N, 3.40. Calcd. for C22H28ClNO.HCl: C, 67.û0; H, 7.41; N, 3.55%.

DES~IPT~ (~*.3R$~-3-t~3-car~QlTlethnx~2 methYlQ~)-~j~
(a) ~*~ yçarbonv~ -cyarlQ;~2~n~
methvlo~v)-~-~henvl~i~in~
This compound was prepared ~om 1-t-butylo~ycar~onyl-3-hydro~r-2-phenylpiperidine (Description 1c) and c~-bromo-m-tolunitriie a~cording to the procedure described in E~ample ld.
lH NMR (360MHz, CDCl3) ~ 1.49 (9H,s, (CH3)3), 1.6-1.72 (2H, 2~ m), 1.87-1.99 (2H, m), 2.72 (lH, dt, J ~ 13, 4Hz, NCE~), 3.80-3.95 (2H, m, CHO ~ NC~, 4.65 (2H, q, J = 12Hz, OCH2), 5.69 (lH, brs, CHPh), 7.1-7.~ (9H, m, ArH).
(b) (2R*.3R*)-3~ bg~b~vphenvlhrlethvln~v-~
phenvl~
The compound of (a) abo~e (1.~g) was dissolved in met~ol (l~ml) and concentr~ed hydrochloric acid (aqueous, 10ml) was ~133:377 WO 93t21181 . PCr/~B93/00788 ;

add~d. The contents were heated at reflu~ for 12h. The solution was cooled and evaporated to leave a brown oil. This was dissolved in methanolic hydrogen chloride and t;he resulting solution was stirred o~ernight, then evaporated. The residue was purified by dispersion between water and ethyl acetate and the organic layer was dried (MgSO4~ and concentrated. The residue was purified by chromatography on silica using a gradient elution of 2%-6% methanol in dichloromethane. The first compound to elute was characterised as the hydrochloride salt by dissolution in methanolic hydr3gen chloIide. The salt was recrystallised from ethyl acetate methanol: mp 206-208C.
(c) (2~*.3R*)-3~ -(Carbometho~v)ph~nv!~me~.h~lQae~)-2-~henvl~i~eridine lH ~ (CDCl3) ~ 1.45-1.71 (2H, m, NCH2CH2CH2), 1.83-2.02 (lH, m, NCH2C~H), 2.12-2.23 (1~, m, NCH2CH~), 2.44 - (lH, bs, NH), 2.77-2.90 (lH, m, NC~I), 3.24-3.34 (lH, m, NC~), 3.61-3.66 (lH, bs, CHO), 3.8-3.83 (lH, d, J = 15Hz, CHPh), 3.90 (3H, s, COOCH3), 4.15 (lH, d, J=12Hz, OCEH), 4.39 (lH, d, J~12Hz, OCHH~, 7.09 (7H, m, ArH), 7.71 (lH, bs, ArH), 7.83-7.89 (lH, m, Ar~I); MS (CI~) m/z 326 (M~+1, 100%).
Fou~d: C, 66.31; H, 6.36; N, 3.80. Calcd. ~or C20H23NO3.HCl: C, 66.38; H, 6.69; N, 3.87%.
, E~ RIPTION 18: (~*.3R*)-3-~-Carb~ nidnghenyl) methylo~ 2 çridir~
The second compound to elute f~om the colurnn described in 17b above was isolated as a colourless oil. lH N M R (360 M H z, C D Cl3) ~ 1.2-2.2 (4 H, m), 2.82 (l H, m c), 3.27 (l H, m c), 3.66 (l H, s), 3.82 (l H, s), 4.16 (l H, d, J = 12 H z, O C~IE), 4.48 (l H, d, J =
12 H z, O CEIEI), 5.53 (l H, brs, C O~IH), 6.18 (lH, brs, GO~EIEI), 7.0-7.4 (9 H? m,~rH).

~ ~ 3 ~ 7 WO 93/21181 PCF/GB~3/00788 DESCRIPTION l9: (2~*.~*)-3-(~2-MethQ~Y-3-ni~rophen~Yl) methvlQ~v)-2-pheny1piperidinium hvdrochloride This compound was prepared f~om the compound of
6 Descnption 1c and 2-methoxy-5-nitrobenzyl bromide, following the procedure described in Descriptions lc-e. mp 246-248C. MS
(CI~) m/z 343 (M++1, 45%~. Found: C, 60.52; H, 5.96; N, 7.45.
Calcd. for ClgHæN2O4.HCl: C, 6Q.24; H, 6.12; N, 7.39%.

PESCRIPTION ~: ~2R$.3R*3-3-((~-Amino-2-methQ~pph,en~
methylo~v)-2-phçnvlpiperidinium hydrockloride The compound of Description 19 (0.342g) was dissolved in methanol (20ml) with hydrochloric acid (1ml, 2N). Palladium on charcoal (50mg) was added and the mixture placed llnder an 15 atrnosphere of hydrogen for lh at room temperature. The solvent was removed in vacuo and the residue basified with sodium hydro~nde (2M). This solution was e~tracted with e~hyl acet~te and the organic extracts were dried (MgSO4) and concentrated to leave a brown oil; this was purified by column 20 chromatography on silica using 8~o methanol in dichlorometh~ne as eluent. The resul~ng oil was characteIised as the salt prepared by t~eatment with methanolic hydrogen chlo~de: mp 241-243C.

2~ The following pipendines were prepared according to the procedures oul~lined in Descriptions 1 and 3, using the appropriate benzyl halide.

12ESCRIPTION 21: (2S.3O-2-Phenvl-~-((3-(~riflu~rometh~
30 ph~vl~

213~77 WO 93/21181 PCI`/GB93/007X~ ' lH NMR (CDCl3) ~ 1.4-2.2 (4H, m), 2.45 (lH, brs), 2.83 (lH, td, J=13Hz and 4Hz), 3.3 (1H, m), 3.64 (lH, d, J=2Hz), 3.82 ~lH, d, J=2~Iz), 4.13 (lH, d, J=12Hz, OC~I), 4.42 (2H, J=12Hz, OCHE), 7.76 (m, 9H, ArH).

I:2ESCRI~ION 22: ~2S.3~-~-((3.4~DichlnrQ~?nenvl)me~lQ~2-2-~henvlpiDeridiniun~ chlorid~
lH NMR (DMSO-d6), 1.65-1.8 (2H, m), 1.8 (lH, m), 2.16 (lH, d, J=12Ez), 3.05 (lH, m), 3.25 (1H, m), 3.83 (lH, s), 4.12 (lH, d, J=12Hz), 4.6 (2H, m), 7.05 (lH, dd, J=7 & 2Hz), 7.28 (lH, d, J=2Hz), 7.35-7.5 (6H, m), 9.05 (1H, br s), 9.8 (}H, br s).

I)I~I~ION 23: (2s~3s)-3-((~.3-DimçthvlI2henvl)methvlo~) 2-~henYl~i~eridini~ ro~hloride Ethyl acetate (10mlj was saturated with hydrogen c~oride by passing HCl gas for ~ min and a solu~on of 0.2~4g of (2S,3S)-1-t-buto~carbonyl-3-t(2,3-dimethylphenyl)metho~y~2-phenylpiperidine (prepared according to Description 3d) in 7ml : of e~yl acetate was added. After s~mng for 2h, the reaction n~ture was concentrated in vacuo. The residual w~ite solid was washed with ether, filtered and dried:to obtain 0.23g of ~- ~: : (2S,3S)-3-((2,3-dimethylphenyl)methylo~y)-2-phenylpiperidinium hyd~ochloride. 'H NMR (DMSO-d6) ~ 1.6-1.9 (3~I, m),~ 1.75 (3H, s),: 2.15 (3H, s), 2.2 (lH, m), 3.05 (1H, m), 3.2~ m), 3.84 (lH, s), 4.0~ (lH, d, J=14Hz), 4.45 (1H, d, J=14Hz), 4 48 (lH, 8), 6.95-7.5 (8H, m), 8.8 (lH, br 8)s 9.4 (lH, br s3.

DE~CRIPTION 24: (2S.3S)-3-(t3-t ~utv!Dhenyl)me~:2-phenvl~ drochln~

~ ~ 3307 ~
w o 93/2ll81 PC~r/G s93/00788 lH ~ME~ (360 M H z, C D Cl3) ~ 1.21 (9 H, s, C(C H3)3), 1.4 (3 H, s), 1.~2-1.67 (2 H, m, C H2), 2.04-2.12 (l H, m, C H ~I), 2.30-2.34 (l H, m, C~H~, 2.93-2.96 ~1 H, m, N C H H), 3.~4 (l H, d?
J=13 H z, N CEI~), 3.72 (l H, s, N C~IC H O~, 4.14 (l H, d, J=2 H z, N C H C H O), 4.28-4.36 (2 H, q, J=13 H z, O C E H), 6.87-6.89 (l H, m, ~rH ), 7.05 (l~I, s, ~rH), 7.11-7.16 (l H, m, ~rH), 7.20-7.34 (4 H, m, ~rH), 7.55-7.58 (2 H, m, ~rH). M S (CI~) rnJz 323 ( M ~+1, 100 %~.

E S C R ~ TIO N ~; (2R*.3 R*)-~-(($.~-Dirnçthylp~ler~yl) met,h~logYL2-nhenvl~ e~dinita~rQ~hloride lH N M]R (360~o H z, C D Cl3) ~ 1.48 (m), 1.62 (m)~ 1.86 (m), 2.20 (s), 2.82 (ddd, J=3Ø 3.0, 12.6 H z)! 3.26 (dt, J=2.15, 2.1~, 12.5 H z), 3.63 (~, 3.78 (s), 4.10 (d, J-12.0 H z), 4.33 (d, J=12.0 H z), 6.31 (s), 7.2-7.4 ( m). M ~ (CI+)rnlz 296 ( M ~+1).

D E ~ C Rr~rlO N _ 26~ R*)-3~ .5:
19i~(~ci~h~ hv~ envl) _ _ m e~hv~Q~Yl-~-(3-chl~ro~hen,Yl)~inç~din~
(a) Methyl-4-~itrobutyrate and 3-chlorobenzaldehyde were react~d L~ a~ analogous manner to that described in Description la to give 2-13-~orop~envl~-ni~ro-6-o~i~ridiae: mp 131-133C. lH NMR (360MHz, CDCl3) ~ 2.26-2.36 (lH, m), 2.60-2.72 (3H, m), 4.66-4.71 (lH, m), 5.24-5.28 (lH, d)~ 6.67 (lH, s), 7.17-
7.40 (4H, m).
(b) The product of part a) was t~eated analogously to that described in Description lb to give 2-(3-chloro~henv!)-3.6-dio~o ~i~e~in~: mp 144-147C. lH NMR (360MEz, CDCl9) ~ 2.8 (4H, m), 5.0 (lH, d), 6.4 (lH, s), 7.22-7.42 (4H, m).

2 ~ 3 ~ ~ 7 ri --WO 93/21181 ` PCI`/(~B93/00788 -c) The product of part b) wa~ treated analogously to tha~
described in Description lc and 3a to give cis-2-(3-chlorophçnvl)-3-hvdro~ eridine tosY!ate salt: mp > 25ûC. lH NMR
(360MHz, CDCl3) ~ 1.60-2.07 (4H, m), 2.28 (3H, s), 3.00-3.11 (lH, m), 4.02 (lH, s), 4.62-4.66 (lH, d), 5.96 (lH, 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-chlorophenyl)-3-hydro~ypipeIidine as a clear, viscous oil. lH
io NMR (360MHz, CDCl3) ~ 1.40 (9H, s), 1.61-1.90 (4H, m), 2.88-3.01 (lH, ddd), 3.93-3.99 (lH, dd), 4.03-4.10 (lH, m), 5.33 (lH, d), 7.20-7.26 (2H, m), 7.34-7.38 (lH, m), 7.47-7.~2 (lH, m). m/z (CI-) 310, 312; m/z (Cl+) 312, 314.
e) l~e ~ product of part d) and 3,5-16 bis(trifluoromethyl3benzy1bromide were treated in an analogous manner to that descnbed in Description ld~ to give cis-3-(13~5-bis(tri~ rometli~henvl~methv!o~r)-l-t-butylo~ b nvl-2-(3-chloroDhenvl)~igqridine. lH N~lR (250MHz, CDCl3) ~ 1.24-1.30 (lE,~ m), lA7 (9H, s), 1.60-2.00 (3H, m), 2.67-2.80 (lH, ddd), 3.81-4.01 (2H, m), 4.8 (2H, s), 5.61-5.67 (lH, d), 7.23-7.27 - (2H, m), 7.39-7.44 (lH, m~j, 7.6 (lH, s), 7.78 ~(2H, s), 7.8 (lH, s).
e product of part e) was treated in an analogous manner to that described in ~Des~iption le to give czs-3-((3.5-- ~ bis(;trifluorome vl)~henvl)methvlo~ 2-(3-chlorophenv!) piDeridine~hvdrochloride~salt, mp = 158C. lH NMR (360~z, DMSO-d6) ~ 1.70-1.96 (4H, ~m), 2.19-2.28 (lH, m), 3.02-3.13 (lH, t ~ ' m), 3.84 (lH, s), 4.35-4.39 (2H, d), 4.60 (lH, s), 4.79-4.85 (2H, d), 7.39-7.44 (3H, m), 7.58 (lH, s), 7.84 (2H, s), 7.97 (lH, s), 9.2 (br s), 10.05 (br s). Found: C, 50.44; H, 4.13; N, 3.01.
C20Hl8ClF6NO.HCl requires C, 50.65; H, 4.04; N, 2.95%. m/z ~CI~), 438, 440.

WO 93/21181 21~ 3 ~ 7 ~ PCr/GB93/00788 DESCRIPTIO~ 2~_2S~3S)-3-~3-Fl~QrQ-5-methylphen~
methylQxv~-2-~hçnvlDiperi~in~
mp 219-221C. lH NMR (360MHz, CDCl3) ~ 1.50-1.68 (2H, m), 2.11-2.15 (lH, m), 2.20 (3H, s, CH3), 2.31-2.35 (lH, m), 2.94-2.98 (1H, m, NCH~), 3.55-3.58 (lH, d, J = 12H~, NCH~), 3.69 (lH, bs, CHO), 4.15-4.18 (lH, m, CHPh), 4.18 (lH, d, J = 13Hz, OC~), 4.33 (lH, d, J = 13Hz, OCHH), 6.47 (lH, d, ArH), 6.59 (lH, s, ArH), 6.66 (lH, d, ArH), 7.26-7.37 (3H, m, ArH), 7.62-7.54 (2H, m, Ar~I). MS (CI+) m/z 300 (M++1, 100%).

DESCRIPTION 28:~3R*)-3-((~ Bisl~rifluorQmethvl)phen-vl) methvlo~-2-methvl-2-(2R*)-2-~hen~2çridine (a) 3,6-Dio~o-2-phenylpipeIidine (Desc~iption lb) ~g) was 1~ dissolved in dimethylformamide (25ml) at 0C. Sodium hydride (873mg, 80% dispersion in oil) was added portionwise and the mi~cture sti~Ted for 15 min. Methyl iodide was added (1.8ml) and the mi3cture was stirred for 12h. The mi~t~e was diluted wit~ water (2~0ml) and e~tracted with ethyl acetate (3 ~). The - 20 - combined organic e~tracts were washed with brine, dried (MgSO4) and concentrated to leave a solid: 3,6-dioxo-2-methyl-2-phenylpiperidine .
(b) The ketone of (a) above (3.2g) was suspel~ded in methanol uIlder nitrogen and the temperat~ire brought to 40C.
Sodium borohydride (0.3g~ was added portionw~se. The mi2~ture was sti~ed for 30 min and then concentrated in uacuo, azeotropillg with tetrahydrofura~. Borane tetrahydrofilran complex (64ml, 1.0M in tetrahydrofuran) was added and the ~re was heated at reflug overnight. The mixtllre was cooled aIld quenched carefillly with methanol, and the m~cture was ~ 3~07 ~ -WO 93/21181 PCI/GB93/00788 `

the~ concentrated in vacuo. The resulting residue was dissolved in ethanol (1OOml) and potassium carbonate (4.2g) was added.
The mi~ture was heated at reflu~ for 12h. The mi~ture was cooled and evaporated and the residue was e~tracted with ethyl acetate and water. The organic extract was washed wi~ brine, dried (MgS04) and evaporated to afford 3-hvdro~v-2-me~h~L2-phenyl~il;?eridine as a~vhit~olid. lH NMR (360MHz, CDC~13) ~
7.79 (2H, d, ArH), 7.40 (2H, t, ArH), 7.15-7.19 (lH, m, ArH), 3.89 (lH, mc), 2.89-3.01 (2H, m), 1.67-1.91 (4H, m)~ 1.39 (3H, s, CH3~.
(c) The alcohol of (b) above (3g) was dissol~ed in dic~loromethane (50ml) and di-t-butyldicarbonate (3.48g) was added. The solution was allowed to stir for 12h. The solution was concentrated in vacuo and the residue was p~ed by 1~ chromatography on silica using ethyl acetate in petrol (20:80) as eluent. This afforded N-t-butylo~ycarbonyl-2-hydro~y-2-methyl-2-phenylpiperidine as a clear oil. IH NMR (250MHz, CDCl3) 1.08 (9H,s, (C~I3)3), 1.80 (3H, s, C~I~3, 1.6-2.0 (4H, m), 3.6-3.74 (2H, m), 3.8-3.92 (lH, m, CHO), 7.2-7.36 (5H, m, ArH).
(d) The alcohol of (c) above (2.2g) was dissolved in dry dimethylfo~amide (12ml). Sodium hydride was added ~0.36g, 60% dispersion i~ oil) portionwise and the mia~ture was allowed to 8tir at room temperature for 30 min. 3,5-Bis(~ uoromethyl)benzyl bromide (3.5g) was added dropwi~e and ~e mi~ture was allowed to ~r for 5h. The mi~ture was diluted wit~ aqueous ammonium chloride, e~tracted with ethyl acetate and the organic e~tract was washed ~nth brine, dried (MgSO4) and evaporated in vacuo. The residue as purified by col~ chromatography on silica using a gradient elution, 100%
30 . petrol to 10% ethyl acetate in petrol as eluant, to af~ord the - product 3-((3,~-bis(trifluoromethyl)phenyl)methylo~

WO 93/21181 2 ~ 3 3 ~ 7 i PC~/GB93/00788 butylo~ycarbonyl-2-methyl-2-phenylpipe~dine as a colourless oil. lH NMR (360MHz, CDCl3~ ~ 1.13 (9H, s ~CH3)33, 1.85 (3H, s, CE3), 1.85-1.99 (4H, m, CH2CH2), 3.48 (lH, brs, NCHH), 3.68-3.76 (lH~ m, NCH~), 3.80-3.86 (lH, m, CHO), 3.8~ (lH, d, J =
12Hz, OCHH), 4.36 (lH, d, J = 12Hz, OCH~), 7.17-7.32 (~H, m, ArH), 7.42 (2H, s, ArH), 7.71 (lH, s, ArH).
(e) The compound of (d) above (2.1g) was dissolved in t;r;fluoroacetic acid (30ml) for 10 min and was then evaporated in vacuo. The residue was dissolved in dichloromethane, washed wit~ sodium hydroxide (2M), water and brine, then dried (MgSO4) and concentrated in v~cuo. Methanolic hydroglen chloride was added to the residue and when dissolved the solvent was evaporated. The residue was trit~ated with e~er to afford ~he product as a white powder: (3R*)-3-((3,5-1~ Bis(trifluoromethyl) phenyl)methylo~y)-2-methyl-(2R*~2-phenyl-piperidine. lH NMR (360MHz, DMSO) ~ 1.67 (3H, s, CH3),~ 1.70 (1:H, m), 1.84-1.91 (lH, m), 1.99-2.06 (2H, m), 3.16 (lH, m), 3.33 (lH, m), 4.19 (lH, s), 4.29 (lH, d, J=12Hz, OCEH), 4.75 (lH, d, J_12Hz, OCH~), 7.29-7.33 (lH, m, ArH), 7.37-7.41 (3H, m, Ar~I), 7.~4 (2H, s, ArH), 7.56 (lH, brs, ArH), 7.89 (1H, S9 ArH). Found: C, 5~.38; H, 4.92; N, 3.08 Calcd. for C2lH2lF6NO:
C9 55.58; H, 4.89; N, 3.09%.

DESCRIPTION 29: (2S.3O-3-((3~4-Dimethv!p~envl~ me~hylo~-Z~ 2-~henvl~
lH N~ (CDCl3) ~ 1.4-1.9 ~3~1, m~, 2.11 (3H, s), 2.17 (3H, B), 2.1-2.3 (lH, m), 2.78 (lH, m), 3.25 (lH, m), 3.60 (lH, s), 3.76 (lH, s), 4.08 (lH, d, J=12Hz), 4.27 (lH, d, J=12Hz), 6.7 (2H, m), 6.92 (lH, d, J=9Hz), 7.2-7.~ (~H, m).

2 ~ 3 ~ O I ~ :
WO 93/21181 PCl/GB93/00788 `: ~-DESCRIPTION 30: _ (2S.3S)-3~ -(isQProl~oxv)p m~thvloxv)-2-~henvlpi~idine lH NMR (250MHz, CDCl3) ~ 1.6-1.9 (3H, m), 1.97 (lH, d, J=7Hz), 2.16 (lH, m), 3.05 (lH, m), 3.3 (lH, m), 3.84 (lH, s), 6 4.09 (lH, d, J=12Hz), 4.41 (lH, d, J_12Hz), 4.44 (lH, m), 4.5 (lH, s), 6.6 (2H, m), 6.72 (lH, m), 7.09 (lH, t, J=8Hz~, 7.3-7.5 (5H, mj.

- DESCRIPTION 31: (2S.3S)-3-((3.5-Bis(trifluoromethvl) ~henYl)me~h~loxv)-2-(3-fluoropheIlvl)~i~eridine lH NMR (360~1Hz, CDGl3) ~1.66-1.9 (3H, m), 2.2-2.3 (lH, m), 2.43-2.5 (lH, m), 3.0-3.2 (lH, m), 3.98 (lH, s), 4.37 (lH, d, J=12Hz), 4.62 (lH, s), 4.79 (lH, d, J=12Hz), 7.04-7.46 (4H, m, ArH), 7.80 (2H, s, ArH), 7.96 (lH, s, ArH).
: I5 -3-Amino-6-~(2R* .3R*)-3-((3.5-Bis(trifluoromethvl)phenyl) methvloxv)-2-ohenvlpigeridin~hnethvll-1.2.4-oxadiazole Hydi~anidine sulphate hydrate (2.3g) was dissolved ~: 20 in water ~and fi~eeze-dried.overnight. Ethanol (35ml) and powdered molecular~: sieves (lg) were added to t~e solid : ~e and t he suspension was stirred under nitrogen for 1 hour. Sodium (670mg) was added to the mi~ture which was ~tirred until all sodium had reacted. The suspension assumed an orange colour àt this ~me and was placed in an ultrasound bath for 15 min. The ester of Desc~iption 2 (1.4g) was added to the mi~ture which was then heated at reflux for 2h. The reaction mi~cture was cooled and filtered through celite.

~. 1.33Qr?7 ~0 93/21181 RCr/GB93/00788 - ~3 -Ethanol was removed in vacuo and the residue was e~tracte~
i~to ethyl acetate and washed with water and brine. The organic layer was dried (MgSO4) and evaporated. The residue was purified on 8ilica using 25% e~hyl acetate in petrol as 5 eluant. This af~orded the product (800mg) as a solid which was recrystallised fi~om ether/~exa~e to a~ord colourless prisms: mp 160-161C. lH NMR (360~Iz, DMSO-d6) d 1.47-1.54 (2H, m, CH2), 1.85-1.9 (1H, m, C~), 2.14-2.17 (lH, m, CH~), 2.35-2.40 (lH, m, C~IN), 2.99-3.02 (lH, m, CH~), 3.3S (lH, d, J =
1~.0Hz, N-C~H-oxadiazole), 3.60 (2H, brs, NCHC O), 3.65 (lH, d, J = 16.0Hz, N-CH~-oxadiazole), 4.06 (lH, d, J = 13.0Hz, OCEH), 4.62 {lH, d, J = 13.0Hz, OCH~), 6.2 (2H, brs, NH2), 7.23-7.31 (3H, m, ArH), 7.42-7.44 (2H, m, ArH), 7.69 (2H, s, ArH), 7.93 (lH, s, ArH); MS (CI+) m/z 601 ((M+1)~, 75%).
Four~d: C, 54.81; H, 4.47; N, 11.2. Calcd. for C23H22F6N4(:)2: C, ~5.20; H, 4.43; N, 11.2%.

5-~(2~* .3R*~-3-((~ .6-Bis(t~ifl~Qmethyl)pher~l) 20 methvlQ~v)-2-1~hen~ eri~LinQlm~h~l~thv~ L~.4-~ZQ~
Acetamideo~ime (117mg) and powdered molecular sieves were suspended in dr~ tetrahydrofilran (10ml) and stirred under nit~ogen for 1 hour. Sodium hydride (63mg of 60~o 25 suspension in oil) was added and the mixture heated to 50C
uDtil all hydrogen evolu~on had ceased. The ester of Des~iption 2 (500ing) was dissolved in tetrahydrofuran (2ml) and added to the above mi~cture. This mi2~ture was heated at reflu~ ~or 2h, cooled, filtered through celite and evaporated in 2 1 3 ~ 3 . I
WO 93/21181 PCI/GB93/007~8;

vacuo. The residue was dissolved in e~hyl acetate and washe~
wi~ water and then brine. The organic layer was dried (MgSO4) and e~aporated in vacuo. The residue was purified by medium pressure chr~matography (Lobar) using 2~o ethyl aceta~e in petrol as eluant. This af~orded the product as a crystalline solid: mp 8~-86C; lH NMR (360MHz, DMSO-d6) d 1.47-1.54 (2H, m, C~I2), 1.85-1.89 (lH, m, C~I), 2.13-2.17 (lH, m, CH~), 2.31 (3H, s, CH3), 2.34-2.40 (lH, m, C~HN), 2.98-3.01 (lH, m, CH~), 3.51 (lH, d, J = 15.0Hz, NC~H-o~adiazolle), 3.60 (2H, s~ NC~C~O), 3.81 (lH, d, J = 15.0Hz, NC~-o~adiazole), 4.06 (lH, d, J - 13.0Hz, OC~H), 4.62 (lH, d, J = 13.0Hz, (:)CH~), 7.26-7.31 (3H, m, ArH), 7.43-7.45 ~2H, m, Ar~I), 7.70 (2H, s, Ar~I), 7.93 (lH, s, Ar~); MS (EI) m/z 500 ((M+l)+, lO0%). Folmd: C, 57.94; H, 4.79; N, 8.23. Calcd. for C24H23F6N3O2: C, ~7.72; E, 4.64; N, 8.41%.

1~
(+) 3-AInir~o-~-r~(2S.3$)-~ bis(~ri~uorome~
~nvl)methvlo~-2-p~lçn~ipe~dino~mç~v~:1.~4-Q~d~
The ~tle ~ompound was prepared ~om the ester of Descrip~on 4 USiIlg ~he procedure described in E~ample 1: mp 138-139C; [a323D = +147.7~ (c=1, MeOH). lH NMR (360MHz, CDCl3) d 1.47-1~50 (2H, m, CH2), 1.85-1.89 (1H, m, C~IEI), 2.14-2.17 (lH, m, CHH3, 2.35-2.41 (lH, m, C~IHN3, 2.99-3.02 (lH, m, CH~), 3.29 (lH, s, NCHCHO), 3.33 (LH, d, J = 15.0Hz, NC~H-het~, 3.65 (lH, d, J = 15.0Hz, NCH~-het), 3.60 (lH, brs, NCHPh), 4.05 (lH, d, J = 13.0Hz, OC~H), 4.62 (lH, d, J =
13.0Hz, OCH~), 6.20 (2H, s, NH2), 7.23-7.31 (3H, m, ArH), 7.42-7.44 (2H, m, ArH~, 7.69 (2H, s, ArH), 7.93 (lH, s, ArH); MS

2 ~ 3 ~ û 7 i (CI+) m/z 501 (M+1+, 75%). Fou~d: C, 54.81; H, 4.47; N, 11.2.
Calcd. for C23~22F6N4O~: C, 54.98; H, 4.54; N, 11.30%.

EX~E 4 3-[~ *.3R*)-3~ -~is(t~iflunromethvl)~henvl~
meth~lo~sT3-2-~henYlni~ridino~methYIl~ini~
hydrochlori~e The compound of Description 1 (410mg), 3-picolyl chlo~ide (167mg) and potassium carbonate were suspended in dimethylformamide (3ml) and the mixture heated at 60C for 12h. The mi~ture was cooled, diluted with water (~ûml) and e~racted wi~h ethyl acetate (2 x lOml). The organic phase was washed with brine, dried (MgSO4) and evaporated. The residue was purified on silica using a gradier~ elu~on of 25-5Q% ethyl acetate in petrol. The product was dissolved in ethereal hydrogen chlo~de to form th~ dihydrochloride salt which was recrystallised ~om benzene: mp 198-200C. lH NMR ~360MHz, DMSO-d,~, 353K) d 1.68-1.82 (2H, m, CH2), 2.09-2.18 ~2E, m, CH2), 3.06 (lE, mc, C~HN), 3.37 (lH, mc, CH~), 3.89 (lH, s, NCHCEO~, 4.16 ~lH, brd, NÇ~H-pyridine), 4.20 (lH, brd, NC~E-pyridine), 4.26 (lH, d, J = 13.0Hz, C~HO), 4.56 (lH, brs, NC~IPh), 4.72 ~lH, d, J _ 13.0Hz, C~O), 7.37-7.41 (3H, m, ArH), 7.60-7.64 (lH, m, ArH), 7.71-7.72 ~2H, m, ArH), 7.86 (lH, s, ArH), 7.89 (2H, s, ArH), 8.08 (lH, d, J _ 8.0Hz, ArH), 8.64 (lH, s, ArE), 8.68 (lH, d, J = 5.0Hz, ArH); MS (CI+) m/z 495 (M+~l, 60%); Found: C, 52.4~; H, 4.90; N, 4.52. Calcd. for C2~3Hæ4F6N2O.2HCl.1.5H2O: C, 52.~4; H, 4.92; N, 4.71%.

213357~!
WO 93/21181 PC~/C~B93/00788 ~E `
2-r~(2R*.~R*)-~ .5-Bi~(~ifluQrom~.thYl~enyl) meth~lox~2-~ ridino~methYll~idinila~
hvdrochloride The compound of Description 1 was reacted with 2-picolyl chloride following the procedure illustrated in Example 4: mp 17~-lB0C. lH NMR (360MHz, DMSO-d6) d 1.65-1.83 (2H9 m, CH2), 2.08-2.15 (2H, m, CH2), 3.16-3.20 (lH, m, C~N), 3.30-3.40 ~lH, m, C~), 3.70 (lH, s, NCHCHO), 4.18 (lH, d, J
= 14.ûHz, C;I~H-pyridine), 4.23 (lH, d, J = 14.0Hz, C~-pyridine), 4.30 (lH, d, J = ~3.0Hz, OCHH), 4.79 ~l~I, d, J =
13.0Hz, OCH~), 4.78 (lH, s, CHPh), 7.24 (lH, d, J = 7.~Hz, ArH), 7.36-7.4 (3H, m, ArH~, 7.47-7.~1 (lH, m, ArH), 7.62 (2H, mc, ArH), 7.85 (lH, dt, J = 7.5, 2.0Hz, ArX), 7.94 (2H, s, ArH), 7.97 (lH, s, ArH), 8.65 (lH, d, J = 7.5Hz, ArH); MS (CI+) m/z 495 (M+1)~, 100%). Found: C, 53.01; H, 4.79; N, 4.69. Calcd. for C26H24F6N2O.2ECI.H2O: C, 53.30; H, 4.82; N, 4.78%.

. ;EXAMPI,E 6 2-r~(2R* .~*~-3~ -Bis~trifl~Qromethvl)pb~nYl~

The compound o f Descnption 1 was reacted with 2-(c~loromethyl)benzimidazole following the procedure illustrated in E~ample 4: mp 162-153C. lH NMR (360MHz, DMSO-d6) d 1.44-1.59 (2H, m, NcH2cH2c~I2)~ 1.85-1.89 (lH, m, CEHCH2N), 2.15-2.18 (2H, m, NCH~+CH~;CH2N), 2.86-2.89 (lH, m, NCH~I), 3.15-3.19 (lH, d, J = 14.0Hz, ~ 1 3 .~ ~ 7 ~
~o 93/21181 pcr/Gss3/oo78 NCHH-imidazole), 3.~7 (lH, s, NCHC~O), 3.63 (lH, s,~
NCHCHO), 3.80-3.84 (lH, d, d = 14.0Hz, NC~H-imidazole), 4.10-4.13 (lE, d, J = 13.0Hz, -OC~I), 4.63-4.66 (lH, d, J =
13.0Hz, -OCHE), 7.07-7.15 (2H, m, ArH), 7.24-7.34 (3H, m, Ar~I), 7.43-7.~2 (2H, m, ArH), 7.60-7.62 (2H, m, ArH), 7.67 (2H, s, ArH), 7.94 (lH, s, ArH), 12.10 (lH~ s, NlI); MS (CI~) m/z 534 ((M+1)+, 100%).

~LE 7 ~-r~2~*.3~*)-3-((3~5-Bis(trifluoromethYl~phçn~l) methvlo~v)-2-~henvl~i~çridinolmeth~71ltetraz~1e The compound of Description 5 (1.Og), triethyl~mine hydrochloride (467mg) and sodium azide (441mg) were dissolved i~ 1-me$hyl-2-pyrrolidinone (6ml) and the reaction m~xttLre was he~ted at reflu~ under nitrogen for 2h. The ~ture was ~hen cooled, and diluted with ice/water (80ml) and acidified to pH = 2 with metha~olic hydrogen chloride. This precipitated the product as a white solid, which was purified on silica using a gradie~t elution of methanol in dichloromethane (0-5%). The product was recrystallised ~om e~er-hexane: mp 114-115C.
lH NMR (360MHz, DMSO-d6) d 1.59-1.&5 (2H, m, NCH2CH2CE2), 2.02-2.22 (2H,~m, NCH2C~I2), 2.39-2.46 ~lH, m, CEEIN), 2.98-3.02 (lH, m, C~IEN), 3.62 (lH, s, NCHCHO), 3.66 (lH, s, NC~ICHO), 3.70-3.74 (lH, d, J = 15.5Hz, NCH;~I-tetrazole), 4.05-4.10 (lH, d, J - 15.5Hz, NCHH-tetrazo1e), 4.08-4.12 (lH, d, J = 12.0Hz, OC~), 4.514.54 (lH, d, J = 12.0Hz, OCHH), 5.30 (lH, s, NH)~ 7.30-7.35 (3H, m, ArH), 7.45-7.47 (2H, m, ArH), 7.51 (2H, B, ArH), 7.74 - (lH" s, Ar~I); MS (CI+) m/z 486 (M++1, 85%). Found: C, 53.14;

~ 3Q~ ~ :

H, 4.~8; N, 13.96. Calcd. for C22H2lF6N5OØ5H2O: C, 53.44; H, 4.48; N, 14.16%.

XA~LE 8 6 2-t~ *.3p~*~ 5-B~rifl~ororl~ç~hvl)phç~l) methv~-2-~enYl~iperidino~methvll-4-me~hYl-~ t}~
An}lydrous acstone ~2ml) and methanol (2ml) ~d tetrabutylammonium perbromide (lllmg) were sti~ed under nitrogen to generate a solution of bromoacetone in situ. The compound of Descriptio~ 6 (160mg) was added to this mi~cture and the resulting solution was stin~ed for 2h. A ~econd equivalent of bromoacetone was added and the ~e wa~
stirred for a filrther 2h. The ~rolatile solvents were removed in vacllo and the residue was dispersed between aqueous 1~ potassium carbonate and ethyl acetate. The organ~c p~se was washed w~th: b~e, dried (Mg~304) and concentrated zn vacuo af~ordi~g a brown oil. This was purified on silica usi~g a gradieIlt elu~on of ethyl acetate in petrol ~10-30%) which gave the product as a ~ear oil: lH NMR (360MHz, CDCl3) 1.51-1.68 (2H, m, G3~2), 1.98-2.22 (2H, m, C;~2), 2.26-2.37 (lH, m, NCEH), 2.38 (3H, s, C~3), 3.18-3.26 (lH, m, NCH;O, 3.47 (lH, d, J =
15.0Hz, NC~IEI), 3.54 (H, bs, C;~O), 3.~8 (H, bs, C~?h), 3.94 (lH, d, J = 15.QEz, NCHa), 4.01 (lH, d, J = 12.5Hz, OC~H), 4.47 (lH, d, J - 12.5~Iz, C)C~H), 6.80 (lH, s, SCE), 7.24-7.35 (3H, m, Ar-H), 7.52-7.54 (2H, m, Ar-H~, 7.58 (2H, s, Ar-H), 7.72 (lH, s, Ar-H); MS (CI+) mlz 515 (M++l, lOO~o). Found C, 58.59;
H, 4.88; N, 5.48 Calc for C25H24F6N2OS: C, 58.36; H, 4.70; N, ~.44%.

~-~ ?3077 WO 93/21181 PCl/GB93/00788 (2R*.3R*)-3-((3 5-~is(trifluoromethvl)~hen~l)metl~
1-(2-furoyl)-2-~henYlpin~dine The compound of Description 1 (400mg) and ~iethylamine (300mg) were dissolved in dichloromethane and the mi~ture was stirred for 10 min at 0C. 2-Furoyl c~loride (1~5mg~ was added to the solu~on and the reac~on mi~ture was stirred for 15 min. The mixture was then washed wit~ brine;
the orga~c layer was separated, dried (MgSO4) and coIlcentrated in vacuo. The residue was purified ~y chromatography on silica using 20~o ethyl acetate in petrol, a~ording a clear oil. lE ~ (360MHz, DMSO-d6) d 1.6-1.8 (2H, m, CH2), 1.9-2.1 (2H, m, CH2), 2.99 (lH, mc, C~IN~, 4.02 (lH, q, J = 5.0Hz, CEO, 4.0-4.2 (lH, m, CH~), 4.78 (lH, d, J
= 13.0Ez, OG~I~, 4.86 (lH9 d, J a 13.0Hz, OCH~), 5.9~ ~lH, s, CEPh), 6.62 (lH, s, furan-H), 6.99 (lH, s, furan-H), 7.25-7.36 (3H, m, ArH~, 7.51-7.54 (2H, m, ArH), 7.83 (lH, s, fura~-H), 7.90 (2H, s, Ar~I), 7.99 (lH, s, ArH3; MS (CI+) m~z 498 (M++1, 20%).

E~0 ,meth~102~-2-~n~ eridinQ\m~hYIl~
The compound of E:gample 9 (340mg) was dissolved in tetrahydrofi~ . To ~his solution was added borane-dimethyl sulfide complex (0.18ml of 10M solu~on) and ~e 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 dissol~ed in methanol 213~77 wo 93/21181 Pcr/GB93/00788 (lOml) aIld potassium carbonate was added (238mg). This~
mi~ture was heated at reflu~ ~or 1 hour; the methanol was removed in vacuo and the residue was dispersed between ethyl acetate and bri~e. The ethyl acetate layer was dried (MgSO4) and evaporated. The residue was purified by chromatography on 8ilica USiIlg 10% e~yl acetate in petrol. The product was recrystallised f~om ether-he~ane: mp 103-104C. lH NMR d 1.4-1.5 (2H, m, CE2GH2), 1.8-1.9 ~lH, m, C~ICH2N), 2.1-2.2 (2H, m, CH~CH2N and CHEIN), 2.95-3.0 (lH, m, CHEN), 3.11-3.15 (lH, d, J = 15.0Hz, NC~H-furan), 3.38 (lH, s, NCHCEO), 3.54-3.58 (lH, d, J = 15.0Hz, NCH~-furan), 3.56 (lH, s, NC~C~O), 4.02-4.06 (lH, d, J = 13.0~Iz, OC~
4.~9-4.62 (1~, d, J = 13.0Hz, OCH;~-), 6.08-6.09 (1H, m, furan ~1), 6.35-6.36 (~, m, furan-~, 7.24-7.32 (3H, m, ArH), 7.46-7.48 (2H, m, ArH), 7.55 (lE, s, furan-~D, 7~68 (2~I, s, ArH), 7.93 (lH, s, ArH); MS (CI+) mlz 48~ (M++1, 100%). Found: C, 62.11; H, 4.80; N, 2.90. Calcd. for C25~23NF6O: C, 62.27; H, 4.83;
N, 2.96.

;~3:XAMPLE 11 -r~12R*.3R*)-3-((3.5-Bi~rifluQro~thvl)~henyl) - methy~ 2-nhen~ eridino}methvll-3-bromo-L2~4-Q~a~iæQ
e hvdrochloride Diisopro yle~ylamine (220~1) was added to a sti~Ted 2~ suspension of the compound of Descnption 1 (200mg) and 5-bromo-3-(chloromethyl)-1,2,4-oxadiazole (99mg) (J.
Heterocyc~ic Chem. 1989, ~, 23`) in dry acetonitrile. The resul~ solutio~ was allowed to stir at room temperatlLre for 48 hrs. After this time the solvem was removed under reduced pressure and ~e residual oil purified by colum~
.

2 1 3 3 a 7 l chromatography on silica using ethyl acetate in hexa~e (20~o) as eluant to af~ord a wa~y solid. Treatment of an e~ereal solu~on of this solid with ethereal hydrogen chlonde yielded a white precipitate. Recrystallisat~on fi~om e~er afforded t~e tit~e compound as an amorphous white solid: mp 100-102C. lH
NMR (360MHz, DMSO-d6) d 1.67-1.70 ~2H, m, CH2), 1.83 (lH, m, CHEI), 2.30 (lH, m, CH~), 2.74 (lH, m, C~N), 3.10 (lH, m9 CH~;N), 3.70 ~lH, d, J = ll.OHz, CH-OCH2), 3 82 (lH, br~, N-C~-Ph~, 4.34 (lH, d, J = 16.0Hz, NCH~-oxadiazole), 4.36 (~H, d, J = ll OHz, OC~EI-~Ar), 4.~8 (lH, d, J = 16.0Hz, NCHH-o~adiazole), 4.73 (lH, d, J = ll OHz, OCX~-Ar~, 7 34-7 42 (5H, m, ArH), 7 68 (2H, s, ArH), 7 73 (lH, s, ~ArH~; MS
(CI+) m/z 564 ((M~1)+, 20%) Found: C, 45.64; H, 3.63; N, 6.70 Calcd. for C23H20N302F6Br HCl: C, 45 98; H, 3 52; NJ 6 99%
1~

5-rl(2R*.3~*~-3-~(3~-Bis(tTifluorQmçth~l)phenYl) o~adiazol~hYdroch~Qri~
The compound of E~ample 11 (169mg~ in dime~yl~ e (33% ill etha~oi) was heated to 40C for 30 min The sol~rent was removed uDder reduced pressure and t;he residue purified by colu~ chromatography on silica using e~hyl acetate in he~ane (20%) as eluant. The compound was dissolved in ether 25 and treated ~nth excess ethereal h~drogen chloride to afford a w~ite precipitate. Recrystallisatio~ om ether af~orded the product as wbite powder (llOmg): mp 179-180C. lH NMR
(360MHz, DMSO-d6) d 1.59 (2~I~ m, CE2), 2.1-2.21 (2H, m, C~Ia)~
2.4-2.45 (lH, m, (:H~N), 3.01 (6H, s, N(C~I3)2), 3.10 (lH, m, ~ ~ 3 3 IJ rl I
WO 93/21181 PCl/GB93tO0788 - ~;2-CEHN), 3.60 (lH, brs, C;E~-o-CH2), 3.70 (lH, d, J = 16.0Hz,~
NCH~-o~adiazole), 3.78 ~lH, d, J = l.OHz, N-CH-Ph), 3.82 ~lH, d, J = 16.0Hz, NC~H-oxadiazole), 4.01 (lH, d~ J = 16.0Hz, O-C~I-Ar), 4.49 (lH, d, J - 16.0Hz, O-CH~-Ar), 7.3 ~3Hs m, ArH), 7.4 (2H, m, ArH), 7.49 (2H, s, ArH), 7.64 (lH, s, ArH); MS
(CI+) mlz (M++l) 529. Found: C, 51.87; H, 4.93; N, 9.62. Calcd.
for C25H26N402F6-HC~ 20. C, 51.~1; H, 5.01; N, 9.61%.

(2~*.3R*!-3-((3.~-Bis(triflunrQmethvl)phen~l)m~thvlo~
2-Dhenvl-l~-thienovl)~eri~i~
The compound of Descrip~on 1 was reacted witJ~
2-thiophenecarbonyl chloride as ou~ined in E~ample 9. The oil obtained after work-up and removal of ~ol~rent was puri~ed by 1~ chromatography on silica, eluting with 10% et~yl acetate in petroleum 0t;her to a~ord the pure product as a clear oiI. lH
~- ~ NMR (250MHz, CDCl3) d 1.6-1.8 (2~I, m, CH2), 2.1-2.2 (2H, m, CH2), 3.0 (lH, m, C~IN), 4.0 (lH, dt, J = ~Hz, 2~Iz, C;~l), 4.1 (1H, brs, C~IN), 4.7 (lH, d, J - 7Hz, CHAr), 4.8 (lH, d, J = 7Hz, CHAr), 6.2 (lH, brs, NGEPh), 7.02 (lH~ dd, J = 1, 2Hz, : . thiophene-H), 7.3-7.44 (4H, m, Ar-H), 7.~ (lH9 dd, J = 1, 3Hz, thiophene-H), 7.6-7.92 (5H, m, Ar-H).

~E~
Z5 ~2~*~3R*)-3:((3.5-~is(trifluoromethvl~hen~l)methylo~v)^
.2-Phenvl-l-(2-thienvlmethyl)~iDeridine The cnmpound of E~ample 13 was reacted with borane dimethylsulfide as described in Example 10. The free base was 2 ~ 3 3 a I .

recrystallised fiom ether and he:Rane to give the product as a~
white crystalline solid. lH N~ (250~Hz, CDCl3~ d 1.44-1.64 (2H, m, CH2), 1.9-2.2 ~2H, m, CH2), 2.24 (lH, d, J = 7Hz, C~N), 3.14 (lH, d, J = 7Hz, C~N), 3.4 (lH, s, C~IO), 3.56 (lH, s, 5 NCHPh), 3.6 (lH, s, C~-thiophe~e), 4.88 (lH, d, J = lOHz, CH-tbiophene), 4.0 (lH, d, J = lOHz, CHAr), 4.24 tlH, d, J
lOHz, C~), 6.7 (lH, d, J = lHz, l~hiophene-H), 6.9 (H, dd, J -2Hz, 3Hz, thiophene H), 7.2 (lH, d, J = 3Hz, thiophene-H), 7.28 (4H, m, Ar-H), 7.5 (3H, m, Ar-H), 7.68 (lH, s, Ar-H). MS mJz 500 (M+, 100%).

~AMPLElE
~-r~(2R*.3R*)-3-((3.6-~ ifluoromethv.l~henvl~ ' m~thvlox~2~enYl~i~eIidino~met~l1-2 .3-dihvdro-4-methvl-3-15 ~ioxo-1.2.4-tri~e hvdrochlQride - A suspension of the compound of Description 7 (0.50g) and methyl isothiocyanate (0.09ml~ in 1-butanol (10~) was heated under reflu~c for 10 min.
1,8-Diaza~icyclo[5.4.0iu~dec-7-ene (0.1ml) was addsd a~ld the 20 reaction mi2cture wa~ heated under reflu~c for 2.6h. The solvent wa~ reved in- vacuo and the~residue was partitioned between water a~d e1~yl acetate. l~e organic layer was dried (MgS04) and~ evaporated. The residue was purified on silica using 5~o met~anol in dichloromethane as eluant to give ~he ~e 25 compouDd. The product (470mg) was characterised as t~e hydro~hloride salt. lH NMR (360MHz, DMSO-d6) d 1.77-1.93 (2H, m, CH2), 2.05-2.22 (lH, m, C~IEI), 2.31 (lH, d, J = 13.5Hz, C~), 3.42 (3H, s, CH3), 3.45-3.51 (lH, m, NCHHCH2), 3.83 (lH, d, J = 12.0Hz, NCH~CH2), 3.97 (lH, brs, C;EI0), 4.24 (lH, d~ J - 15.5Hz, N-C~H-het), 4.32 (lH, d, J = 15.5H2, 2 1 ~ 3 ~ 7 ~ . -wo 93/21181 Pcr/Gsg3/oo788 N-C~-het3, 4.33 (lH, d, J = 12.~Hz, O-C~I), 4.76 (lH, s~, NCH), 4.80 (lH, d, J = 12.5Hz, O-CH~.), 7.42-7.60 (3H, m, Ar~I), 7.69 (2H, brs, ArH), 7.85 (2H, s, ArH), 7.89 (lH, s, ArH), 9.l5 (lH, brs, NH); MS (FAB) mlz 630 ((M+l)+, 13%).

~ [~2~*~-3-~-Bis(trifluoromethyl)ph~3 meth~L2-phenvll~i~eridinQ~methvlLL2 .4-triazol~
The compouIld of Description 1 (l.Og), anhydrous potassium carbonate ~0.94g) and N-formyl-2-cbloroacetamidohydrazone (0.46g3, (prepared according to Yanagisawa, I., J. Med. Chem. l984, ~Z, 849) were: heated to 60C in anhydrous dimethylformamide ~or 3h, followed by - hea~g at 130C for 12h. The reaction mi~ture was cooled, dilut:ed wi~ el;hyI acetate (lOOml) and washed with water, (3 x 20ml). ~e ethyl acetate layer was dried (MgSO4), filtered a~d :~ evaporated to ~give a brown oil. ~his was purified on silica using ethyl acetate in petrol (70:30) as eluant. This afforded the product as a white solid. lH NMR (2~0M~z, CDCl3) d 1.6 (2H, 2û m, CH2), 1.95-2.24 (2H, m, G-H2), 2.34 (lH, m, NC~EI), 3.06 (lH, m, NC~), 3.44 (lH, :d, NCH~-t:riazole), 3.6 (lH, bs, CEO), 3.6 (lE, bs,:NC~?h), 3.8 (lH, d, N-C~H-triazole), 4.04 (lH, d, OC~I-Ar), 4.50 (lH, d, OCHEAr), 7.3 (3H, m, ArH), 7.44 (2H, m, ArH), 7.5 (2H, s, ArH), 7.7 (lH, s, Ar~I~, 7.9 (lH, s, 1~iazole-H). MS ~CI~) m/z 485 (M*~l, 35%).

WO 93/21181 PCI/(~93/00788 ~L~
6-~l(2R* ~R*)-~3~5-Bis(~hvl)~hen~
methYIo~v)-2-~ eridi~ methvll-~ 3-dihysLr thio~o-1.2.4-tTiazole The compound of De~crip~on 7, potassium thiocyanate (0.45g) and conc. hydrochloric acid (2.3ml) in water (12ml) were heated under reflu~ for 2h. Af~er coolirlg, solid 80dium hydro~de was added uIltil pH = 8 and the aqueous layer was ea~tracted wi~ ethyl acetate. The organic layer wa~ dried (MgSO4), filtered and etraporated to give the s~ru.de semi-w~rbazide which wa~ heated at reflw~ in 2N sodium hydro~ide solu~ion (lOml) for 2h. Aflcer coolîng the solution was a~dified ~ pX 6-6 and the product extrac~ed in~o ethyl acetate.
The organic l~yer ~as dri~d (MgSO4), filtered and evaporated.
The crude triazole was chromatographed on silica eluting with 40% ethyl acetate/60-80 petroleum ether to gi~e the title compound as a white solid. lH NMR (250MHz7 CDCl3) d 1.6 (~I, m, CH2~, 1.9-2.3 (3H, m, CH2 + NC~I), 2.95 (lH, bd, NC~I), 3.16 (lH, d, N-C~I-Het), 3.20 (lH, bs, CHO), 3.6 ~lH, bs, NC~'h)~ 3.78 (lH, d, N~ -Het), 4.1 (lH, d, C~H-Ar), 4.58 (l~I, d, C~-Ar), 7.32 (5H, m, ArH), 7.5 (2H, s, Ar-H), 7.78 (lE, s, ArH). MS (FAB) m/z 517 ~M++1, 80%).

~:l~PLEI~
5-rl(2R*~*)~ ~3.~is(triflugrom~thvl~hen~
methYlo~r~-2-p~nyll~i~eridinQlmethvll-~-meth~etrazole Tbe compou~d of Example 7 (500mg) was suspended in water (4ml) a~d sodium hydro~ide (44mg) added. This was 2133~7'!

heated to an exterI~al temperature of 96C and dimethyl~
sulphate (66mg~ added. The reaction mi~ture was allowed to stir under Ditrogen at 96C for lh aflcer which time stirring was continued for 24h at 5C. Af'cer this time, the product was e~tracted into dichloromethane and washed wit~ water and brine. The organic layer was dried (MgSO4) and e~aporated.
The residue was purified on silica using medium pres~ure chromatography (Lobar), and eluted with 25% ethyl acetate in petrol. The first compo~d to be eluted was isolated, and thiB
af~orded the product (50mg) as a crystalline solid, which was recrystallised t~om etherlhexane to afford white crystals: mp 139-141C. lH N~ (360MHz, DMSO) d 1.44-1.51 (2H, m, CH2), 1.79-1.82 (lH, m, CH~), 2.12-2.15 (lH, m, C~I), 2.19-2.25 ~1H, m, CHHN), 2.97-3.00 (1H, m, CH~), 3.37 ~lH, d, J _ 14Hz, N-CH~-tetrazole), 3.62 (lH, s, NCHCHO~, 3.58 (lH, s, NC33:CHO), 3.81 (lH, d, J = 14Hz, N-C~H-tetrazolej, 4.03 (lH, d, J = 13Ez, OCH~), 4.31 (3H, s, CH3), 4.60 (lH, d, J
= 13Hz, OC~), 7.23-7.33 (3H, m, ArH), 7.49-7.51 (2H, m, A~H), 7.68 (2H, s, Ar~I), 7.93 (lH, s, ArH); MS (CI+) mlz ~00 ((M+13+, 100%). FouIld: C, 56.~6; H, 4.76; N, 14.20. Calculated for C23H23N5OF6: C, 55.31; H, 4.64; N, 14.02%.

~,~
5-r!(2R*.3R*~ ~hen~
~ethvlo~)-2-Dh~ eridinolInet~ll-l-methyltetrazol~
The title compound was prepared as desc~ed in E~ample 18. Dunng pu~ification, the second compound to be eluted was isolated, and this af~orded t~e product (120mg) as a crysta~ e solid, whic~ was recrystallised f~om ether/he~ane to wo 93/2ll8l 2 1~ 3 a i ~ pcr/GBs3/oo788 a~ord yellow crystals: mp 75-77C. lH NMR (360MHz, DMSO~
d 1.51-1.55 (2H, m, CH2), 1.84-1.87 (lH, m, CH~), 2.12-2.16 (lH, m, C~I), 2.31-2.37 (lH, m, CH~), 2.81-2.84 (lH, m, C~HN), 3.52 (lH, d, J = 15Hz, NCH~-te~), 3.54 (lH, s, NCHC~O), 3.60 (lH, s, NCECHO), 3.82 (lH, d, d = 14Hz, NC~H-tet), 3.84 (3H, s, CH3), 4.14 (lH, d, J = 13Hz, OCH~I), 4.85 (lH, d, J = 13Hz, OC~H), 7.26-7.32 (3H, m, ArH), 7.45-7.48 (2H, m, ArH), 7.74 (2H, s, ArH), 7.94 (lH, s, ArH~; MS (CI~) m/z ~00 ((M+1)+, 2û%).
E~LE 20 _-r~(2R*.3R*)-3-((3 5-Bis~triflu~rQ~ethvl)~hen~l) me~ylo~)-2-~henYl~i~eridino~methY11-5-dimethvlamino-1.2.4-a) 5-Dime~h~damino-3-(chloromethYl)-1~.4-thiadiazole A 801ution of dimethylamine in ethanol (0.5ml x 33%) was added to a s~rred suspension of 5-chloro-3-(chloromethyl)-1,2,4-t~iadi~zole (540mg) (J. Goerdeler, Chem. Ber. 1957, ~Q, p 182 OI ICI EP 0006679) and potassium carbonate (1.Og) in m~thanol. The solu~on waæ stir~ed at room temperature for three hours, and then the solvent removed under reduced pressure. The residue was taken up iIl et~yl acetate (40ml), washed~ water (20ml) and brine (20ml). The organic layers were dried (MgSo4j, filtered and the solvent removed to afford a yellow gum. Elash chromatagraphy using 10% ethyl acetate in hesane as eluent, a~orded ~he product as a yellow oil (330mg).
lH NMR (360MHz, CDCl3) d 3.15 (6~I, s, N(C~I3)2), 4.51 (2H, s, Cl-CE2); MS (CI+) m/z 178 ((M+1)+, 9~%).
b) A solution of the compound of Descrip~on 1 (223mg), 5-dimet~hylan~ino-3~chloromethyl)-1,2,4-~adiazole (100mg) Z1~3'`~7 1 .WO 93/21181 PCl`/GB93/0078B

and diisopropylethylamine (0.2ml) were heated at reflu~ in drg acetonit~rile for ~hree hours. The reaction was ~hen allowed to cool to room temperature and the solvent removed under reduced pressure. Pulification of 1~e residue by flash chromatography (40% EtOAc/nHex) gave a yellow gum.
Recrys~isation firom n-hexane af~orded ~he product as yellow plates: mp 144-145C. lH NMR (360MHz, CDCl3) d 1.57 ~2H, m, C~2), 2.11 (3H, m, CE2+C~I), 2.42 (lH, m, CHE), 3.11 (6H, s, N(C;E3)2), 3.20 (lH, m, C;~-OCH2), 3.47 (lH, d, J ~ 14.5Hz, C~-thiadiazole), 3.56 (lH, m, C~h), 3.75 (lH, d, J = 14.5Hz, CHH-thiadiazole), 4.03 (lH, d, J = 10.6Hz, OC~H-Ar), 4.45 (lH, d, J = 10.5Hz, OCH~-Ar), 7.30 (3H, m, ArH), 7.51 (2H, s, ArH), 7.53 (2H, m, ArH), 7.69 (lH, s, ArH); MS (CI~) m/z 545 ((M+1)+, 60%). Fo~d: C, 55.12; H, 4.76; N, 10.38. Calcd. for C25H20F6N4SO: C, 65.14; H, 4.81; N, 10.30~o.

E~LE 21 2-r~(2R*.3R*)-3-1(3.5-Bis(tnfluoromethvl)phe~
methvlo~vi-2-~henvl~il)eridinollnç~vlL4.7-~ime~Ylb~nzo~azole A solution of 2-(chloromethyl)-4,7-dimethylbenzo~azole (285mg) in dry acetonitrile (lO~nl) was added to a solution of the compound of Description 1 in dry acetonit~ile (10ml) containiDg diisopropylethylamine~(O.4ml). The resulting mi~ture was heated at reflulc for three hours, cooled to room temperature and the residue purified by flash chromatography on silica gel using 20% ethyl acetaWn-he~ane~as eluant. Re~ysta~lisation of the isolated mate~al f~om n-hexane af~orded the product as white needles: mp 109-110C lH NMR (CDCl3) 1.49-1.53 (2H, m, C~I2), 1.~6-1.60 (l~I, m, C~I), 2.03-2.09 (lH, m, CHE), 2.10-2.16 (lH, m, CHHN), 2.36-2.40 (lH, m, CEHN), 2.47 (3H, wo 93/2l~81 2 1 ~ 3 ~ 7 ~ Pcr/GBg3/00788 s, Ar-C~33, 2.~4 ~3X, s, ArC~3), 3.24 (lH, m, C;~N), 3.59 ~lH, m,~
CHOCH2), 3.67 (lH, d, J = 12.0Hz, N-CHH-benzo~azole), 3.79 (lH, d, J - 12.0Hz, N-CH~-benzoxazole), 3.96 ~lH, d, J =
10.OHz, OC~I), 4.47 (lH, d, J = 10.0Hz, OCH~), 6.99 (2H, s, ArH), 7.32 (3H, m, ArH), 7.54 (2H, s, ArH), 7.~7 (2H, m, ArH), 7.71 (lH, s, ArH); MS (CI+) m/z 563 ((M+1)+, 70%~. Found: C, 64.09; H, 5.04; N, 5.12. Calcd for C3OH28N202F6: C, 64.05t H, 5.01; M, 5.00%.

E~LE ~2 2-rl(2R*.3R~ (trifluorom~thvl)~hen~l) methvlo~v~-2-nhenvl~iperidino~methv!lbenzo~a~ole Thi8 compound was prepared following t~e procedure described in E~ample 21, using 2-(chloromethyl)benzoxazole a~
the alkylating agent: mp 95-97C. lH NMR (CDCl3) d 1.47-1.60 (2H, m, G~I2), 2.06-2.19 (2H, m, C~2)~ 2.42-2.56 ~lH, dd, lH~ J =
6.0, 4.0Hz, NC~I), 3.26 (lH, dd, J = 4.0, 2.0Hz, NCH~), 3.61 (lH, s, CHO), 3.66 (lH, d, J _ 15.0Hz, NC~H-benzo~azole), 3.66 (lH, d, J - 2.0Hz, CHPh), 4.û2 (lH, d, J = 15.0Hz, CHII~ zoxazole), 4.04 (lH, d, J = 12.0Hz, OC~I), 4.48 (lH, d, J = 12.0Hz, OC~I), 7.26-7.67 (12H, m, Ar~I); MS (CI+) m/z 535 ((M+l)+ 6~%). Foulld: C, 62.36; H, 4.67; N, 5.27. Calc for ~28~24F6N22- 141~2 C, 62.39; H, 4.58; N, 5.20%.

~AMPLE~ 23 4-rS(2S~ is(trifluo~om~thvl)phenvl~methvlo~v)-2~ ~thvllox~zole 1,3-o~azole-4-carboxaldehyde was prepared following th~
procedure described by J. Hodges, W. Patt and C. Connolly, L Or~. Chem. 1991, ~i, 449-4~2.

a) 4-(Hvdro~methYl~-1.3-o~le 1,3-Oxazole-4-carbo:~aldehyde (0.38g) was dissolved in anhydrous methanol and stirred lmder nitrogen; SOdillm borohydride (0.074g) was added carefully. Af~;er 1 hour no starting material was present by TLC using 50% e~yl acetate in he~ane as eluent. The methanol was removed by rotary e~raporator (water ba~h temp 40C). The residue was purified by chromatography on silica eluting with 100~o diethyl ether. This a~orded ~e alcohol (0.27g) a~ a white solid. lH NMR d (360 MHz, CDCl3~ 2.93 (O~I), 4.63 (2H, s, C~20H), 7.64 (lH, s, oxazole-H), 7.90 (lHf s, o~azole-H).
- b) 4-rl(2S.3S)-3-(~.~is(tnfluornmeth~l)phe~
met~ h ~llo~azole 4-(Hydro~ymethyl)-1,3-o~azole (0.13g) was dissolved in anhydrous dichloromethane (4ml) under an at;mosphere of nitrogen. Triethylamine (0.19ml) andp-toluenesulfonyl chlonde (0.13g~ were added to the react;ion mi~cture which was stirred for 1 hour at room te~peratureO .A further port;ion of p-toluenesulfonyl chloride (0.13g~ and a catalytic amount of dimethylaminopyridine were added to the reac~on mi~cture.
The compoulld of Description 3 (1.2g, ~ee base) was dissolved in dimethylformamide (5ml) and was added to the reaction n~ture followed by triethylamine (0.19ml). The mi~ture was heated at 60C for 2h and the resull;ing mi~ture was diluted with water (60ml) and e~tracted with dichloromethane (3 ~c 20ml). The combined organic layers were dried (MgSO4) and conceIltrated in vacuo to af~ord a yellow oil. This was purified by WO 93/211Xl ~ 3 3 'J ~ 1~ PCI/GB93/00788 chromatography on silica gel using a gradient elu~on of 30-60 ether in he~e to af~ord the title compound as a white solid.
This was recrystallised ~om ether/hexane: mp 102-104C. lH
NMR ~360MHz, CDCl3) d 1.46-1.64 (lH, m, NCH2CH2CE~I), 6 1.7-1.87 (lH, m, NCH2CH2CH~), 1.96-2.20 (2H, m, NCH2C~2), 2.32-2.48 (lH, m, NC~I), 3.20-3.46 (3H, m, NCH~ +
NC~I-ogazole ~ C~OCH2Ar), 3.55 (lH,. ~rs, C~Ph), 3.68 (lH, d, J = 14.5Hz, NCH~-o~azole), 4.01 (lH, d, J = 11.5Hz, OCEHAr), 4.46 (lH, d, J = 11.5Hz, OCH~Ar), 7.24-7.58 (8H, m, ArH~, 7.70 (lH, s, ArH), 7.80 (lH, s, ArH); MS (CI+) 485 (M+ +
1, lOO~b) E~IPLE 24 ,2-r~(2S.3S~3-~(3.5-Bis~tnflllQromçthvl)~h~nvl~e~h~lQ~2-2-Dhenvll2u2e~ methYll~v~e a) 2-(Chloromethv!~vrazine 2-MethylpyraziDe (lg) wa~ dissolved in carbon tet~achloride (~Oml) under nitrogen. N-Chlorosucci~imide (1.42g) and ~eIlzoyl pero~ide (50mg) were added and the mi~cture was: heated at reflu~ for 24h. The reaction mi~ture was cooled aIld filtered through celite and :~e filtrate was co~ trated in vacuo. The resulting oil was purified on silica using 30% ethyl acetate i~ petrol. lH N~l[R (360MHz, CDCl3) d 4.72 (2H, s, CH2Cl), 8.56 (2H, s, ArH), 8.76 (~I, s, ArH).
2~ b) 2-r~ 3-((3.5-~is(trifluoromet,h~
met~rlo~ h~lpi~eridino~met~ll~e 2-(Chloromet~yl)pyraz:ine (0.17g), potassium carbQnate (0.6g) and l~he compound of Des iption 3 (0.35g~ were suspend~d i~ dimet~ylformamide ~3ml); the react;ion mi2ture was heated at 60C for 12h. The mi~ture was cooled, di.luted - - :

2 13 3 ~3 7 r~ ~
WO 93/21181 PCl/GB93/00788 with water (30ml) and e~tracted with ethyl acetate (2 ~ 20rnl).~ :
The combined organic layers were washed with brine, dried (MgSO4) and concentrated in vacuo to ~ord a brown oil. The produc:t was purified by column chromatography on 8ilica gel using a gradient elution of 15-35% ethyl acetate in he~ane. This afforded the product as a white solid, which was recrystallised f~om pentane to gi~e colourless crystals: mp 108-110C . lH
NMR (360MHz, DMSO-d6) d 1.42-1.60 (2H, m NCH2CH2CH2), 1.77-1.92 (lH, m, NCH2CHH), 2~13-2.25 (2H, m, NC~I +
NCH2CHE), 2.84-2.92 (lH, m, NCH~), 3.12 (lH, d, J = 14.0Hz, NC;~I-pyrazine), 3.55 (lH, m? CHO), 3.63 (lH, m, C~h~, 3.78 (lH, d, 14.0Hz, NC~;-pyrazine), 4.1I (lH, d, J = 13.0Hz, OC~HAr), 4.64 (lH, d, J = 13.0Hz, OCHHAr), 7.20-7.33 (3H, m, ArH), 7.49-7.~6 (2H, m, ArE), 7.71 (2H, s, ArH), 7.93 (lH, s, ArH), 8.48-8.63 (3H, m, ArH); MS (CI~) 496 (M+~1, 60%).
Found: C, 60.90; H, 4.86; N, 8.48. Calcd. for C25H23F6N3O: C, 60.60; H, 4.68; N, 8.48%.

~E
4-r~f2S.3S)-3-(~3.6-~is(trifluoromethv!~?~enyl)met~ylo~r)-2-phenvl~ eridino~Inethvll-2-meth~rl-l.~-~hiazoli~m ~(Chloromethyl)-2-methylthiazole hydrochlo~ide (83mg) wa~ added to a suspeIlsion of the compound of Descr.iption 3 and potassium carbonate in dimethylformamide ~5ml). The resulting~ mi~ture was heated at 60C for 18h, cooled to room temperature and diluted with water (50ml). This solution was egtracted with ethyl acetate (2 x 25ml) and the combined organic e~racts were washed with water (2 x 20ml), brine (20ml), dried (MgSO4) and filtered. The resultLng solution was 2 ~ el ~
WO 93/21181 PCl/GB93/00788 evaporated under reduced pressure to afford a yellow oil. This~
was purified by medium pressure liquid chromatography using 50% ethyl acetate in he~ane to af~ord the product as a white solid. This was tIeated with e~hereal hydrogen chloride and 6 recrystallised ~om methyl-t-butyl e~her to afford ~he title compound: mp 58-60C. lH NMR (360MHz, DMSO-d6) d 1.71 (2H, m, CH2), 2.11 (2H, mc, CH2~, 2.49 (lH, m, C~), 2.69 (3H, s, Ar-C~3), 3.15 (lH, m, CH~), 3.54 (lH, m, CHO), 4.12 (2H, m, CE2-~hiazole), 4.16 (lH! d, J = 10.0Hz, OC~IAr), 4.68 (lH, brs, C~Ph), 4.76 (lH, d, J = 10.0Hz, OCH~Ar), 7.40-7.43 (5H, m, ArH), 7.64 (lH, brs, ArH), 7.92 (2H, s, ArH), 7.97 (lH, s, ArH); MS (CI+) m/z 515 (M+ + 1). Found: C, 48.17; H, 4.76; N, 4.52. Calcd. for C2sH24F6N20S.2HCl.2H20: C, 48.16; H, 4.85; N, 4.49~o.
EXAMPLE ~6 3-r~2S.3~3~is~uoromet,hv~2h~ methvlOE~v~:
2-~henvlDi~eridi~lm~ .4-o2adiazQle.hvdrn~hl~
3-(Chloromethyl)-1,2,4-.os~adiazole (270mg) was added to a 20 rapidly stirred suspension of the compound of De~cription 3 and potassium carbonate in dimethylformamide (10ml). The reaction misture heated at 60C for 4h, cooled to room temperature and ~uted with water (50ml). The aqueous solution was e~racted with ethyl acetate (3 x 50ml) and 1he 2~ organic ext2~acts were combined, washed with water (3 ~ 50ml), brine ~50ml), dried (MgSO4) and filtered. The resulting solution was concentrated u~der reduced pressure and purified by column chromatography on silica gel using 20% ethyl acetate in he~cane as eluent. The resulting oil was treated ~nth ethereal 30 hydrogen chlonde to affiord the li~e co~pound as a white 2-1 ~ 3 ~

WO 93/21181 PCl`/GB93/00788 `

powder: mp 74-7~C. lH NMR (360MHz, DMSO-d~;~ d 1.62 (2H, m, CH2), 1.37-2.1 (2H, m, CH2~, 2.50 (lH, m, C~IN), 3.16 (1H, m, C~HN), 3.51 (lH, m, CHQ), 3.69-3.72 (3H, m, CH2-oxadiazole + C~Ph), 4.14 (lH, d, J = 10.0Hz, OC;~IAr~, 4.70 (lH, d, J = 10.0H2, OCH~Ar), 7.32 (3H, m, ArH), 7.45 (2H, m, ArH), 7.78 ~3H, m, ArH), 7.94 (lH, s, ~rH).

~L~7 3-r~(2S.~)-3-((3~ l~uorometh~ 2he~ methvlo~n~
2-phen~ ipe~no~thvll-~^iodo-1.~thiadiaz~
a) ~-IodQ-3-(iodo~h~-thiadi~ol~
Sodium iodide (eaccess) was added to a StiITed solution of 5-chloro-3-(c~loromethyl)-1,2,4-thiadiazole (3.0g) (J. Goerdeler, Chem. Ber. 1957, ~Q, 182) in dry butanone ~15ml). The resulting solutio~ was heated at reflux for four hours, cooled to room temperature and filtered. The filt~ate was diluted with water (20ml) and e2tracted ~nth ethyl acetate (50ml). The ethyl acetate layer was dried (MgSO4), filtered and co~centrated ~n vacuo to afford a red oil, which was used in ~e following - 20 reactio~ without filrther purification.
b) 3-r~(2S.3S~-3-((3.~-~is(trifluorQm~thel~h~
methYl~- }~nvl~i.~di~Q~mçthyl~ iod~-l.2 .4-thi~i~ol~
~iisopropyle~hyla~e (116mg) was added to a stirred solu~on of ~-iodo^3-(iodomethyl)-1,2,4,thiadiazole (160mg) and the compou~d of Descnption 3 (200mg) in dry acetonitrile (lOml). The resulting solution was sti~ed at room temperature for 18h. The reaction mi~ture was filtered and the solvent was removed in vacuo to af~ord a red oil. This was purified using columll chromatography on silica gel using 20% ethyl acetate in he~ane as eluent. Tbis affiorded the product as a powder: mp 21~3~7 ~
WO 93/21181 PCr/GB93/00788 98-101C. lH NMR (360MHz, CDCl3) d 1.~ (3H, m,~
NCH2CX2C~2 + NCH2C~H), 2.13 (2H, m, NCH2CH~ ~ NC~I), 2.42 (lH, m, CH~, 3.21 (lH, m, CHO~, 3.69 ~2H, m, C~Ph +
C~H-thiadiazole), 4.02 (2H, m, CH~-thiadiazole ~ OC~H), 4.48 (lH, d, J = 8.0Hz, OCH~), 7.32 (5H, m ArH), 7.51 (2H, s Ar~I), 7.70 ~lH, s, ArH).

3-r~2S~)-3-((~-Bis(trifluQrometh~ henYl)meth~lo~r2-2-Dhenylpi~r~dinQ~m~thv~ 1.2~hi~sliazol~chlori~e, Sodium borohydride (280mg) was added to a stirred solution of the compound of E~ample 27 (500mg) and palladium (II) chloride (280mgj in ~ methanol (2~ml). Ihe re6ulting mi~ture w~s stirred for 30 min and then filtered through celite;
the filtrate was concentrated in vacuo. The solid residue thus obtained was dissol~ed in ethyl acetate and the sollltion was washed with water (10ml), the organic extract was dried (MgSO4), filtered and concentrated in uac~o to af~ord a yellow oil. Treatment of this oil ~nth ethereal hydrogen chloride a~orded t;he title compou~d as a white powder: mp 89-90C. lH
NMR (360~z, DMSO-d6) d 1.79 (2H, m, CH2), 1.9-2.20 (3H, m, C~ + NCH2C~I2), 2.6 (lH, m, C~IN), 3.8 (lH, bm, C~IC)), 3.89 (lH, brs, C~IPh), 4.2-4.3 (3H, m, CE2-thiadiazole ~ OC~I), 4.76 (lH, d, J = 9.0Hz, OC~), 7.39 (3H, m, ArH), 7.55 (2H, m, ArH), 7.89 (2H, s, ArH), 8.32 (lH, s, ArH), 10.32 (lH, s, N-C~-~;); MS (CI+) m/z 502 (M+ + 1). Found: C, 49.31; H, 4.09;
N, 7.18%. Galcd. for C23H2lF6N3OS.HCl.1.25H2O: C, 49.48; H, 4.37; N, 7.52%.
-2 1 3 3 ~ 7 .' ~ -r~-~ Bi~ifluolQm~thvl~nhçtlyl~et~-2-phenvl~?çridi~ol~t~ll-~-m~thoxv- 1 ~2~4-thi~i~QIe hvdrochloride Sodium metho~de (34mg) was added to a stirred solution of the compound of 13~ample 27 (200mg) in methaIlol (5ml). The solu~on was heated at reflug for 2h, cooled to room temperature and 'Lhe solvent removed under reduced pressure af~ording a solid residue. The solid was dissolved in ethyl acetate (15ml~, a~d the organic phase was wa~hed ~th water (20ml), separated, dried (MgSO4) and the solvent was removed under reduced pressure. The residual solid was treated with ethereal hydroge~ chloride a~d the resul~ng solid was recrystalli6ed from ethyl acetate to a~ord the product as white needles: mp 74-7~C. lH ~ (360MXz, DMSO-d6) d 1.56 (2H, m, CH2), 1.73 (lH, m, C~IH), 2.09 (2H, m C;~I2), 2.43 (1H, m, CHE), 3.20 (lE, m, C;~IO), 3.49 (2H, m, CEPh + C~;-~iadiazole), 3.76 (lH, m, CHH-thiadiazole), 4.02 (lH, d, J = 10.0Hz, oc~IEI)~ 4.14 (3H, s, OC~3), 4.4~ (lH, d, J = 10.0Hz, OCHE), 7.30 (3H, m ArH), 7.51 (4H, brs, A~H), 7.64 (lH, s, ArH); MS (CI+) m/z ~32 (M+ + 1). Found: C, 49.89; H, 4.10; N, 7.41. Calcd. for C2~H23F6N3O2S-HCl O.~E2O: C, 49.96; H~ 4.37; N, 7.28%.

~LE 30 2~
2~ 1Di2eridinQ~m~th~11-1.2.~-tri~nl~ dihvdrQ~hlQ~Q
The title compou~d was prepared according to t~e procedure desc2ibed in E~ample 16, using t~e compound of 2~ 3~77 WO 93/21181 PCI/GB93/0078$

DescIiption 3 as 8tarting material. The f~ee base wa~ treated with ethereal hydrogen chloride to af~ord the product as a white crystalline solid: mp (~ee base) 209-210~C . Found: C, 49.36;
H, 4.67; N, 10.05. Calcd. for C23H22F6N40.2HCl: C, 49.56; H, 4.34; N, 10.05%.

2-~henvlDi~eIidinn~methvll 2.~-dihvdro-(4H~:~hioxo-1æ~-triazole hvdrochloride The title compound was prepared according to 1~he procedure desc~bed in E~ample 17, using the oompound of Deacrip~ion 8 as a 6ta~g material. This af~orded the product as a white so~d which was treated with ethereal hydrogen chlonde to yield the crystalline hydro~oride: mp 154-157C.
Found: C, 46.~9; H, 4.52, N, 9.26; Cl, 5.84. Calcd. for - - C23H~,F6N40.HGl.2H20: C, 46.90; H, 4.62; N, 9.51; Cl, 6.02%.

E~LE 32 2-ri(2s.3s)-~(3~5-Bis(trifluorome~h~1henvl)methylo2 2-~henvloi~in~thvll-L*-tQluen~ulfonYl)imi~

(a) ~-(p-Toluenesul~im~ole-2-c~Lo~aldehvd~.
Imidazole-2-catbo~aldehyde (1.92g) was suspe~ded in dichloromethane (20ml). p-Toluenesulfonyl chloride (3.8g) and trie~hylamine (2.8ml) were added to the mi~ture which was stirred at room temperature for 12 hours. The resulting ~lurry was diluted with water and the org~nic layer was washed ~vith 2 ~ 3 v 3 7 1 WO 93/21181 PCI/GB93/00788 `

- 7~ -brine, dried (MgSO4) and filtered. The dichloromethane layer wa~ co~centrated in vacuo and the residue was purified by column chromatography on silica using 50% ethyl acetate in he~:ane as eluent. This a~orded the product as a yellow oil 6 which crystallised on sta~ding. 'H NMR (360MHz, CDCl3) d 2.44 (3H, s, ArCH~), 7.31 (lH, d, J=1.5Hz, imidazole-H), 7.37 (2H, d, J=8.0Hz, ArH), 7.83 (lH, d, J=1.5Hz? imidazole-H~, 8.00 (2H, d, J_8.0Hz, ArH)~ 9.78 (lE, s, CHO). MS (CI+) mlz 251 (M++l).
(b) 2-(E~n~meth~lLl~gluenesulfon~)imi~azol~
The aldehyde of (a) above (3g) was dissolved in methanol (15ml) and sodium borohydride (114mg) was added portionwise.
Thi6 601utio~ was stirred for 10 min. Methanol was removed in vac~o and the residue was dispersed between e~yl acetate and 1~ water. The organic layer was separated, dried (MgS04) and filtered and ~he solvent was removed in vacuo to a~ord a cry~talline solid. lH ~ (250MHz, CDCl3) d 2.42 (3H, s, ArCH93, 4.84 (2H, s, CH20), 7.00 (lH, d, J=1.5Hz, dazole-H), 7.36 (2H, d, J=8.0Hz, ArH), 7.40 (lH, d, J=1.5Hz, imidazole-H), 7.84 (2H, d, J=8.0Hz, ArH).
(c) ((~D~ol~es~ nvl~imidazol-2-vl)meth~l The alcohol described in (b) above (12.6mg) was dissolved in dicbloromethane (2.5ml) and triethylamine (.07ml). Thi~
aolu~o~ was cooled to 0C. Methanesulfonyl chloride (.04ml) was added to the solution dropwise. After s~rring for 10 mins the solution was diluted with water and the organic layer was separated, dried (MgS04), filtered and the solvent removed in vacuo to yield a white solid which was used in the followiDg reaclio~ out filrther purification. lH NMR (250MHz, CDCl3) d 2.44 (3H, s, A~H), 2.94 (3H, s, 5O2CH3), 5.51 (2H, 8, ?~133~7~
wo 93/~1181 pcr/GBg3/oo788 CE2So2), 7.08 (lH, d, J=1.5Hz, imidazole-H), 7.40 (2H, d, J=8.0Hz, ArH), 7.49 ~lH, d, J=1.5Hz, imidazole-H), 7.92 (2H, d, J-8.0Hz, ArH).
(d) ((N-p-Toluenesulfonyl)imidazol-2-yl)methylmethane-sulfonate (1.6g~ was added to a suspension of the compound of Descrip~ion 3 (2.47g) and potassium carbonate (800mg) in dimethylformamide (1Oml) and the resulting mii~ture was heated at 100C for 2h. The mi~ture was cooled, diluted with water (1OOml) and e~tracted with ethyl acetate (3 x 20ml). The organic e~tracts were combined, washed with brine, dried (MgSO4) and concentrated in vacuo. This afforded a colourles~
oil which was purified by colum~ chromatography on silica using 25-30% ethyl acetate in hexane. This af~orded 'che product as a white crystalline solid whieh was recrystallised ~om dic~oromethane/pet~ol: mp 12~-126C . lH NMR (360MEz, DMSO-d63 d 1.4-1.5 (lH, m, NCH2CH2C~I), 1.5-1.67 (lH, m, NCH2CH2CH~I), 1.8-2.0 (lH, m, NCH2C~I), 2.06-2.1 (lH, m, NCH2CH~), 2.35 (3H, s, CH3), 2.4 (lH, mc, NC~H), 2.7-2.86 (l~I, m, NCH~;), 3.50 (lH, d, J = 14.ûHz, C~I-imidazole), 3.~6 (lH, brs, CHoj, 3.76 (lH, d, J = 1.5Hz, CHPh), 4.08 ~lH, d, J =
14.0Hz, CH~-imidazole), 4.09 (lH, d, J = 12.0Hz, OCHH), 4.48 (1H, d, J = 12.0Hz, OCH~), 6.96 (lH, d, J = 1.0Hz, imidazole-H), 7.1~ (2H, d, J = 8.5Hz, Ar~), 7.2-7.3 (3H, m, ArH), 7.34 ~lH, d, J = 1.0Hz, imidazole-H), 7.46-7.~8 (2H, m, ~H), 7.60 (2H, s, ArH), 7.71 (lH, ArH), 7.79 (2~I, d, J = 8.~Hz, ArH);
MS (CI+) m/z 638 (M~ + 1). Fo~d: C, 58.48; H, 4.78; N, 6.72;
S, 4.81. Calcd. for C3lH29F6N303S: C, 68.39; H, 4.58; N, 6.~9; S, 5.03%.

r ~J '3 ~i 3 3 7 l wo 93/21181 pcr/GB93/oo788 ~L~
- 2-r~2~ ,-((3~5-Bis(t~aQromethvl)~h~nvUmethYl~-,2-phenvlpi~er~ r~hvllimida~ol~ dihYdrochlQ~d.~
The compound of Example 32 was dissolved in dichloromethane and ethereal hydrogen ~loride was added.
The resulting solution wa~ 6tirred for 30 minutes whereupon the title compou~d crystallised f~om solution. This was removed by filt~ation and recrystallised ~om ethyl acetate/methanol to afford the title compound as a white crystalline compound. lH
NMR (360MHz, D20) d 1.61-1.74 (lH, m, C~H), 1.76-1.88 (lH, m, C~I), 2.04-2.21 (2H, m, CH2), 3.07-3.23 (lH, m, NC~H), 3.41-3.51 (l H, m, N C ~ ), 3.66 (l H, s, C H O), 4O09 (l H, d, J=1300 H z, O C ~ ), 4.25 (l H, d, J=15.5 H z, C~ mQidazole), 4.30 (l H, æ, C~l~?h), 4.39 (l H, d, J=15.5 H z, C H El-inoidazole), 4.~5 (l H, d, J_13.0 H z, O C E~3D, 7.1-7.2 (3 H, m,f~rH), 7.2-7.3 (2 H, m, ~rH), 7.38 (2 H, s, innidazole-H), 7.48 (2 H, s, ~r~I), 7.51 (l H, s, ArH); M S (Cr~) no/z 484 (Mr~l, 25 %). Fou~ld: C, 50.32; H, 4.92;
N, 7.23; Cl, 12.58. Calcd. for C24H ~ F6N30.2 H CI.H 2 0: C, 50.18;
H, 4.74; N, 7.32; Cl, 12.34 %.
~0 ~E~
4~[~S.~ .~is~romet~l)~nvl~t~ylo~-~-phen~l~i~di~m~l~imi~azQle di~ochlorid~
TSi8 was prepared follo~nng the procedure described for 25 E~ample 33 u~g the compound of Description 3 and 4-(hydro~ymethyl)i~idazole as . starting materials. Thi8 a~orded the ~le compuu~d as a white crystalline compound:
mp 20~210C. lH NMR (360MHz, D20) d 1.73 (lH, m, 2`~ 33~7~

NCH2CH2C~I), 1.94-2.06 ~lH, m, NCH2CH2CH~), 2.22-2.40 (2H, m, NCH2C~2), 3.33 (lH, mc, NC~H), 3.70-3.81 (lH, m, NCH~), 3.97 (lH, brs, CHO), 4.30 (lH, d, J_12.5Hz, OC~I), 4.42(2H, s, NCH2-imidazole), 4.50 (lH, SJ NC~Ph), 4.75 (lH, d, J=12.5Hz, OCHE), 7.48 (6H,brs,ArH~imidazole-H)~ 7.74 (2H, s, ArH), 7.9~ (lH, s, ArH), 8.80 (lH, s, imidazole-H); MS (CI~) m/z 484 (M~+l Found: C, 50.22; H, 4.82; N, 7.18; Cl, 12.49.
Calcd. for C24H23F6N3O 2HCl-H2O: C~ ~0-18; H~ 4 74; N~ 7-32; C, 1~.34%
E~IP~E~5 5-rl(2R*.3R*~ is(tnfluorQm~h~n~l) m~lo~ 2-~hçn~ éridiDo~methvll-~ 3-dihYdro-t4H~
1.2:~iazole hvdrochloridç

(a) N-Carbometho~v-2-c~loroacetamidrazonc Sodium metho2~ide (0.032g) was added :to a solution of c~oroacetonitrile (1.26ml) in anhydrous methanol (15ml) at 0C. The reaction mi~ure was stirred at room temperature for 0.5 hour and then neutralised ~ ace~c acid (0.034ml).
Met~yl hydraz;inocarboxylate (1.79g) was added and the reac~on mi~ture stirred at room temperature for 0.5 hour. The - solution was concen~ated in vacuo to gi~e the title compound as a~ orange solid. MS (CI)+ m/z lff6.
(b) The compound of Description 1 (0.50g) was stirred ~nth N-carbometho~y-2-c~loroacetamidrazone (0.19g) a~d potas~ium carbonate (0.47g) in dimethyIformamide (10ml) at 70C for 18 hours. The reaction mixture was then stiITed at 140C for 1 hour. AflGer cooling, the m~tenal was pa~tioned betwee~ e~yl acetate and water. The organic layer was washed W0~ 1 PCI`/GB93/00788 with water, dried (MgSO4), filtered and concentrated. The residue was purified by chromatography on silica using 5%
methanol in ethyl acetate as eluent. The product was recrystalli~ed f~om ethyl acetate~petrol to give the title 6 compouI~d as a white crystalline solid. This was characterised as its hydrochloride salt: mp 168-172C. MS (CI)~ mlz 500 ((M+1)+, 18%). Fo~d: C, 50.65; H, 4.43; N, 10.22; Cl, 6.71.
Calcd- fior C23H24N42.sF6Cl: C, 50.60; H, 4.43; N, 10.26; Cl, 6.49%.
EX~PI,E36 5-rl(2R* 3R*)-3-((3.~trifluoromethvl)~henvl) meth~lo~r)-2-~henvl~ridi~ethvll-3-(N~N-dimeth~laTnino)-1 .2.4-thiadiazole ~a) ~-(N.N-Dimethvlamin~LL~-o~atbiazo~irL2-nn~
A solution of chlorocarbonylsulfenyl chloride (11.5g) in acetonit2ile was added to a suspension of N,N-dimethylurea (25.0g~ in acetonitrile (200ml), over a period of 20 minutes. The reaction m~re was stirred for 1 hour at 23C, then filtered.
20 Methanol (20ml) was added to ~e filtrate to decompose e~cess chlorocarbonylsulfenyl chlonde. The solvents were removed in VQCUo. The residue was purified by chromatography on silica usi~g dichloromethane in hexane (3:1) to afford the product as a yellow oil. lH NMR (250MHz? CDCl~) d 3.04 (6H, s, (CH3)2); MS
25 (CI+) m/z 164 (M++NH4+) (Chl~romethvl)-3-~N.N-dimethvla~no)thiadi~znle C~loroacetonitrile (1.3ml) in dimethylformamide (1ml) was heated to 150-155C a~d B-(N,N-dimethylamino)-1,3,4-oxat~iazolin-2-one (1.Og) was added in portions. Aflcer 6 30 minutes the reaction mi~cture was cooled and concentrated in WO 93/21181 2 1 ~3 3 0 7 I PCT/GB93/00788 uacuo. The residue was purified by chromatography on silica using he~ane/e~hyl acetate (9:1) as eluent. This af~orded the product as a white crystalline solid. lH NMR (250MHz, CDCl3) d 3.19 (6H, s, (CH3)2), 4.82 ~2H, s, CH2); MS (GI+) m/z 178 ~c) 5-r~(2R*~R~ (3.5-Bis~trifluoromethYl)~henyl).
meth~rlo~v)-2-phenvlDi~eri,diaQ~me~yll-3-(~-dimethylamin~:
L2.4-thiadiazole hvdrochlQri~
The compound of Description 1 was reacted with 5-(chloromethyl)-3-(N,N-dimethylamino)thiadiazole according to the procedure described in Example 4. This af~orded the ti~e compound as a white solid: mp 160-161C; lE NMR (36ûMHz, DMSO-d6 + TFA) d 1.69-1.87 (2H, m, CH2), 2.01-2.26 (2H, m, CH2), 3.10 (6H, s, (CH3)2), 3.22-3.34 (lH, m, CEH), 3.64-3.72 (lH, m, GEH), 3.90 (lH, s, CHO), 4.26-4.34 (2H, m, CH2), 4.61 (lH, d, 3=20.0Hz, OC~H), 4.76-4.82 (2H, m, OCH~ + C~Ph), -~ 7.36-7.62 (5H, m, ArH), 7.87 (2H, s, ArH), 7.99 (lH, s, ArH).

,5-rl(~S)-3-~ trifllloro~ethYl)phenvl)~ethvlo~
2-~he ~nvl~iperidino~Inethvlltet~Qle This compound was prepared according to the procedure descnbed i~ E~nple 7, using the compound of Desc2ipt;io~ 9 as a ~ ng material: mp 179-181~. MS (CI+j mtz 486 (MH+, 35%). Found: C, 54.61; H, 4.53; N, 14.37. Calcd. for C22H2~F6N5O: C, 54.43; H, 4.36; N, 14.43%.

~J133:~7 ~/
WO 93/211XI P~/GBg3/00788 EXA~L~
5-r~ hen~met~d~
2-Dhenvl~ip~ridino~methvlL2-methvltetrazole This compound was prepared according to the procedure 5 described in Example 18 using the compound of Example 37 as a starting material. This af~orded ~e title compound as a white cryst~lline material: mp 158-159C. MS (CI+) mlz 500 (MH~, 70%). Found: C, 55.84; H, 4.66, N, 14.13. Calcd. ~r C23H23F6N50: C, 55.31; H, 4.64; N, 14.û2%.
EXA~PLE 39 ~ -rl(2S.3~ 3-((3.~-~;~nfluQ.~o~ethvl)phenvl)me$hylo~rsr)-2-1?henvl~ridino~methvll~-mçthvltetrazol~
Ihis compou~d was prepared according to ~he procedure 15 described in E~ample 19 usi~g the compound of Example 37 as a staFting m~terial. This af~orded t~e title compourld as a clear oil. MS ~CI+) 500 (MH+, 40%). Found: C, 66.27; H 4.69; N, 13.67. Calcd. for C23H23F6N5O~ 5.31; H, 4.64; N, 14.02~o.
.. ~ .
; 3~LE ~0 ,3-rl(2~(3 5-~is(trifluQrQm~thvl)ph~nyl~ethvl~
2-~henvl~ipcri~ino~t~idazine (a) 3-(HYdro~vlneth~?1~.2-1; vnd~
1,2-py~idazine-3-carboxaldehyde (0.89g) (G. Heinisch, E.
Luszczak and M. Pailer, Mh. Chem 104, 1372 (1973)) was dissol~red in water and sodium borohydride (0.081g) was added carefillly. After 1 hour ~o star~g material was present by TLC

~ ~3~77 VO 93~21181 PCI/GB93/00788 USiDg 10% methanol in dichloromethane as eluent. The water was removed in vacuo to afford a ~m. The gum was e~tracted with dichloromethane, the combined organics were dned (MgSO4) and concentrated in vacuo to afford the alcohol as a 5 solid, which was used in 1~he following experiment without further purification. lH NMR (360MHz, CDCl3) d 5.04 (2H, s, C;E~20H), 7.54 (lH, dd, pyridazine-H), 7~65 ~lH, dd, pyridazine-H), 9.17 (lH, dd, pyridazine-H).
(b~ 3-r~(2S.3S~:~(3.5-Bis~trifluQrnmethvl~Qnvl 10 methYlogyL2-~envl~ erislinolmethvll~ridazine 3-(Hydro~ymethyl)-1,2-pyridazine was dissolved in anhydrous dichloromethane ~der an atmosphere of nitrogen and cooled ;n an icelwater bath. Triethyl~ne (0.68ml~ and methanesulfonyl chlo ide (0.378ml) were added and the reaction 1~ stirred for 1 hour. No starting material was present by TLC
using 5% methanol in dic~loromethane as eluent. The solvent was removed in vacuo to afford a solid. The compound of Description 3 (0.48g of free base) was dissol~ed in dimethylformamide (5ml) and added to the solid followed by potassium carbonate (0.85g). The mi~ture was heated at 60C
for 12 hours then poured into water (75ml), extracted with ethyl acetate (3x40ml), dried (MgSO4) and concentrated to afford a brown oil. This wàs pi~ified by chromatography OIl sîlica gel using a gradient elution of 10-30% ethyl acetate in petrol.
2~ Fur~er p~cation was Garried out by medium pressure chromatography; elut;ion with 50/60 ethyl acetate/petrol affiorded thetitleco~pouIldasawhitesolid: mplll-113C. lHNMR d (360MHz, DMSO-d6) 1.43-1.66 (2H, m, NCH2CH2C~2), 1.77-1.91 (lH, m, NCH2C~IEI), 2.13-2.24 (2H, m, NCH9;CH~), 2.75-2.87 (lH, NCHH), 3.27-3.36 (lH, d, NC~I-pyridazine), 3.~7-3.70 (2H, NC;EIPh + C~IO), 3.83-3.93 (lH, d, I2 1 3 ~ i3 r! ri~
WO 93/21181 Pcr/GBg3/00788;

-~6-NC~I-pyridazine), 4.14 (lH, d, J-13Hz, OC~IAr), 4.66 (lH, d, J=13Hz, OCH~Ar), 7.23-7.35 (3H, m, Ar-H), 7.50-7.56 (2H, m, ArH), 7.66 (2H, s, pyridazine-H), 7.71 (2H, s, Ar30, 7.94 (lH, s, ArH), 9.11 (lH, m, 4H) MS (CI~) m/z 496 ((M+~1), 30%) ~LE~

2-r~2s~3s)-3-((3 .5-Bis(trifluoromethv!)phenyl)methylQ~.
2-phenvlpiperidino~methvll-1.3.5-triazin~
The compound of Descrip~on 3 (2g), chloroacetamidine hydrochloride (1.17g) and diisopropylethylamine (3.17ml) were -dissolYed in acetoI~itrile (1Oml) and the resulting mi~ture was stirred at 60C, under nitrogen, for 12h. The resulting mi~ture was evaporated aIld the residue was dispersed bet~reen ethyl acetate and water. The aqueous layer was e~tracted with ethyl acetate (2x50ml) and dichloromethane (2x50ml). The combined organic fractions were washed with b~ine, d~ed (MgSO4) and evaporated. The residue was purified by chromatography on silica usiIlg 5% methanol in dichloromethane and gradient elution to 10% methanolJ 1% aqueous ammonia in dichloromethane. Thi~ af~orded ~he intennediate amidine as a semi-solid matenal, which was not further purified.
The intermediate ami~ne (2g) and 1,3,5-triazine (0.35g) 26 were di~solved ilI acetonitrile (7ml) and heated at reflux for 12h.
The solution was cooled a~d evaporated and the residue was purified by chromatography on silica using 50% petrol in ethyl acetate as eluent. This af~orded the product as a crystalline solid which was recrystallised from hexane: mp 117-119C. lH NMR
(360MHz, D~SO-d6) ~ 1.41-1.60 (2H, m, NCH2CH2C~2)~ 1.81-1.94 (lH, m, NCH2CEH), 2.12-2.21 (lH, m, NCH2CH~), 2.34-.. 21.?~07 ~ WO 93/21181 PCI`/GB93/0~788 2.41 (l H, m, N C~I H), 2.99-3.06 (l H, m, C H~I), 3.26-3.30 (l H~
J=15.0 H z, N C~H-triazine), 3.61 (l H, bs, C~IO), 3.71 (l H, bs, C~p?h), 3.80 (l H, d, J=15.0 H z, N C H H~triazine)j 4~08 (l H, d, J=13.0Hz, OC~HAr), 4.~3 (lH, 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 (l H, s, ~rH), 9.20 (2 H, s, triazine-H). MS (CI~) rn/z, 497 ( M ~+1, 100~

E~A~n?L E 42 5-r~(2S.3S)-3-((3-t-Bu~1-6-meth~l~henYl)me~h ~lQ:~v)-2-(phenvlpi~endino~meth~1~2.3-d;hvdro-3-oxo-1.2.4-tna~

The compou~d of Descnption 10 was reacted according to ~he procedure descnbed in E~ample 35 to af~ord the ~tle compound as a crystalline solid: mp 18~-187C. lH NMR
(360MHz, CDCl3) ~ 1.22 (lOH, m, C(CH3)3 + NCH2CH2C~I), 1.38-1.68 (2H, m, NCH2C~CHO, 1.98-2.26 ~5H, m, CH3 +
NG~EIC~, 2.89 (lH, d, J=15.0Hz, NC~I-triazole), 2.96-3.04 (l H, m,~:N C ~ I), 3.as l1 H, bs, C H O), 3.56 (l H, bs, C ~ Ph), 3.65 : (1 H, J=l5.0 H z, N C~I H-triazole), 4.13 (l H, d, J=12.0 H z, O C~1~3~r), 4.28 (1~I, d, J=12.0 H z, O C H ~ r), 6.53 (1 H, s, ~rH).
6.89 (1~I, s, ~rH3, 7.00 (l H, s, Ar~I), 7.26-7.38 (3 H, m, ~r~
7.45-7.50 (2 H, m, ~rH). M S (CI~) rk/z 435 ( M ++1, 60 %). Fol~n d:
C, 72.10; H, 7.94; N, 13.05. Calcd for C~BH 34N402: C, 71.86; H, 7.89; N, 12.89 %.

L91YL?L E 43 2-r~ .3S)-3-((3 6-ni~hlQro~erLylknl~thv!o~rv!-2-(gheILylDi~eIidino~m eth~Ilimidazole dihy~rochlori~

2 3 ~ 3 3 . ~

.

The compound of Des~iption 11 wa~ reacted according to the procedure desc~ibed in E~amples 32/33, to afford the ~tle compound: mp 129-131C. lH NMR (360MHz, D~SO-d6) S 1.84-1.98 (2H, m, NCH2CH2C 2)~ 2.14-2.24 (lH, m, NCH2CHE), 2.44-2.62 (lH, m, NCH2C~I), 3.09-3.20 (1H, m, NC;E~H), 3.69-3.86 (2H, m, NCH~ ~ CHO), 4.25 (lH, d, J=13.0Hz, OC~IAr), 4.53 ~lH, d, J=13.0Hz, OCH~Ar), 4.83 (lH, d, J=15.0Hz, NC~I-imidazole), 4.91 (1~, bs, C~Ph), 5.14 (1H, d, J_15Hz, NCH~-imidazole), 7.16-7.48 (lOH, m, ArH), 7.84 (lH, bs, N-H).
MS (CI~) m/z 415 (M+1+, 70%). Found: C, 50.71; H, 5.28; N, 8.05.
CæH23CI2N~0.2HCl.2H20 requires: C, 5û.30; H, 5.56; N, 7.99%.

5-~(2~.3S~3-((3-Chloro-5-methYlp~nvl)meth~irlo~)-~-Phenvl~i~eridino~meth~11-2.3-dihvdro-~-o~o-1.2~4-tria~le The compou~d of Desc~ip~on 12 was reacted according to t~e procedure described in Example 35 to af~ord the tit le compound as a white crystalline solid: mp 227-228C. lH N~
(360MHz9 DMSO-d6) ~ 1.35-1.55 (2H, m, NCH2CH2C~2), 1.78-1.88 (lH, m, NCH2C~I), 2.06-2.13 (2H, m, NC~HC~), 2.20 (3H, s, CH3), 2.73 (lH, d, J=14.0Hz, NC~H-tnazole), 2.89 llH, d, J=ll.OHz, NCH~), 3.32-3.39 (lH, m~ CHO), 3.42 (lH, d, J=14.0Ez, NCH~I-triazole), 3.47 (lH, s, GEPh), 3.86 (lH, d, J=12.0Hz~ OC~:), 4.29 (lH, d, J_12.0Hz, OCH~), 6.65 (lH, s, ArH), 6.79 (lH, s, ArH), 7.07 (lH, s, ArH), 7.25-7.34 (3H, m, ArH), 7.51-7~53 (2H, m, ArH). MS (CI~) m/z 412 (M~+l, 20%).
Found: C, 64.30; H, 6.13; N, 13.67. C22H25ClN402 requires: C, 63.99; H, 6.10; N, 13.57%.

2~ 33?7r~
WO 93/21181 PCI`/GB93/00788 ~ .

s-rl(2$~ 5-B.is(trifluQro~t~y~hQnYl)nlethylo~y-2-(dil)henvlmethYl)l)~rrolidino~nle~hyll-2.~-~ihvdro-3-oxQ-l.~

The compound of Desc~iption 13 was reacted with N-carbometho~cy-2-chloroacetamidrazone according to the procedure described in E~ample 35 to af~ord the product as a white crystalline solid. lH NMR (250MHz, CI)Cl3) ~ 1.92 (2H~
m), 2.62 (lH, m), 2.90 ~lH, d, J=1~Hz), 3.14 (2H, m), 3.78 (2H~
m), 4.08 (lH, m)~ 4.28 (2H, m), 7.1-7.4 (lOH, m, Ar~, 7.48 (2H, s, ArH), 7.77 (lH, s, ArH). MS ((:~I+) m/z 577 (M~1, 10Q%).

EXA~PL~

2-(dil~vlm~k~rroli~in~ethv.11-2.3-dihy~ oxo-1.2.4:

- The compound of Description 14 was react~d with N-earbometho~ 2-chloroace~midrazone accordi~g to the procedure de~mbed in Example 35 to afford the title compou~d as a whi~e crystalli~e sol~d. lH ~MR (360M~Iz, CDCI3) ~ 2.00 (2H, m), 2.69 (lH, m), 3.03 (lH, t, J-7.5Hz~, 3.26 (lH, d~
J=14.5Hz), 3.32 ~lH, d, J=14.5Hz), 3.68 (2H, s), 3.76 (lH, d, J=3.~Hz~, 4.31 (lH, d, J=12.5Hz), 4.42 (lH, d, J=12.5Hz), 7.40-7.19 (lOH, m, ArH), 7.64 (2H, s, ArH), 7.76 (lH, s, ArH). MS
(CI~) m/z ~77 (M~l, 100%).

2 1 ~ 7 ,' wo 93/21181 P~/GB~3tOO788 3-r~2~i~3~)-3-((3.5-Dichloro~hen,Yl)methyloxv~
henvlmethyl)~v~ olidino~methvll~1.2~-tri~

The compound of Description 15 was reacted with N-formyl-2-chloroacetamidrazone according to the procedure in E~ample 16 to afford the title compound as a crystalline solid:
mp l28-l29C. lH ~ (360MHz, DMSO-d6~ ~ 1.65 (l~I, brs), 1.76 (lH, brs), 3.lO (2H, m), 3.61 (lH, d, J=12.0Hz), 3.92 (lH, brs~, 4.01 (lH, brs3, 4.22 (2H, m~, 7.02 (2H, d, 3=l.8Hz~ ArH), 7.10 ~lH, m, ArH), 7.14 (3H, m, ArH), 7.22 (2H, t, ArH), 7.39 (2H, d, A~I), 7.46 (3H, m, ArH~. M5 (CI~) m/z 493 (M++l, 60%).
Found: C, 65.95; H, 5.22; N, 11.33. Calcd for C27H26Cl2N40: C, l~ 65.72; H, 5.3l; N, 11.35%.

E~L~4 5-rJ(2S~3S)-3-((3-t-Butvl-5-c~oro~n~
ghenvl~ie~}~ R~

The compound of Descrip~on 16 was reacted with N-carbometho~y-2-chloroaGetamidrazone, according to the procedure described i~ Example 3~, to af~ord the titl~ compouIld as a white ~yst~lline solid: mp 181-182C. MS ~CI+) m/z 455 (M~+l, 100%). Fou~d: C, 65.99; ~I, 6.87; N, 12.31. Calcd for C25H~IlClN40: C, 66.47; H, 6.91; N, 12.45%.

2~ 33~7 l WO 93/211~1 PCI~GB93/0&1788 ~L~

5-rf(2~;.3S)-~-((3-~3is(tri~uoromethYl)~?henvl)methylo~-2-henYl~iperidiIlo~mçt~ll-~ dih~dro-3-oxQ~ 4-tri~nle 5 hYdro~hlori~

The ti~e compound was prepared according to the procedure described in E~cample 35, using the compound of Descrip~on 3 as 6tartiIlg material. The hydrochloride salt was 10 recryst~sed f~om ethyl acetate-methanol to give a wbite cryst~e solid: mp 26~^266C. lH NMR (360MHz, DMSO-d6 +
TFA) ~1.75-1.95 (2H, m, CH2), 2.04-2.30 (2H, m, CH2), 3.20-3.32 (lH, m, NC~H~, 3.58-3.69 (lH, m, NCH~), 3.90 ~lH, d, J=15.0Hz, NG~H-triazole), 3.93 ~lH, ~, CHO), 3.94 (lH, d, J=15.0Hz, NCHE-triazole), 4.30 (lH, d, J-12.0Hz9 OCH~), 4.73 (lH, bs, C~h), 4.80 (lH, d, J=12.0Hz, OC~), 7.42 (3H, brs, .4rH), 7.56 (2H, brs, ArH), 7.89 (2H, s, ArH), 7.95 (lH, s, ~rH).
MS (CI~) m/z 501 (M~1), 60%). Found: C, 51.41; H, 4.15; N, 10.58; Cl, 6.46. Calcd for C23H22F6N40.HCl: C, 61.45; H, 4.3~; N, ~0 10.44; Cl, 6.60~b.

;~LE~L

~vl~hen~l~meth~lQ~)-25 2-~l~e~yl-L2~azQI~
hvdrochloride .
The compound of E:~ample 30 ~O.~g) was dissol~red in methanol in a tube. Sodium (0.03g~ and iodomethane (O.Q75ml) 30 were added and the container was sealed. The resulting solution was heated at 6~C for lh, cooled and evaporated. The residlle 2 ~ 3 3 3 7 .
WO 93J21181 PCrt(:~B93/00788 wa6 suspended between water and ethyl acetate. The organic layer was dried (MgSO4), filtered and the solver~ removed in vacuo. The residue was purified by chromatography on silica using ethyl acetate as eluent. This afforded ~e product as a colourless oil, which was converted to ~he hydrochloride salt by addition of ethereal hydrogen chloride. The salt was re~ystallised ~om ether/petrol. lH NMR (360MHz, DM5O-d6) 1.70-1.84 (2H, m, CH2), 2.12-2.51 (2H, m, CH2), 3.36 (3H, s, NCH3), 3.52 (lH, brs, C~EN), 3 73 (lH, brs, CH~), 3.87 (lH, io s, CHO), 4.25 (2H, m, CE~-triazole), 4.28 (lH, d, OC~HAr), -4.65 (lH, brs, NC~Ph), 4.78 (lH, d, OCH~Ar), 7.41 (3H, s, ArH), 7.6û (2H, brs, Ar~I), 7.93 (2H, s, ArH), 7.96 (lH, s, ArH),
8.05 (lH, s, CE_NH (triazole)); MS (CI+) mJz 499 (M~+1, 85~o).

E~l 3-r~(2S.3S)-3-((3.~is(trifluoromethYl)phenyl)met~Ylo~n)-~-phenvl~i~idinolmethvll-5-pheny~-1 2.4-o~i~l~
hYdro~hloride The compound of Descrip~on 3 was reacted wit~ 3-c~loromethyl-5-phenyl-1,2,4-oxadiazole accordi3lg to the p~ocedur~ described in Example 26. The product was charæterised as its hydrochloride salt: mp 88-90C. lH NMR
(360MEz, CDCl3, ~ee base) ~ 1.50-1.64 (2H, m, CH2), 2.06-2.22 (2H, m, CH2), 2.44-2.56 (lH, m, C~IN), 3.18-3.28 (lH, m, CH~IN), 3.60 (lH, s, CHO), 3.66-3.74 (lH, d, J=15.0Hz, NC~I-oxadiazole), 3.78 (lH, s, CHPh), 3.88-3.98 (lH, d, J=15.0Hz, NCH~-oxadiazole), 4.02-4.10 (lH, d, J=12.0Hz, OC~HAr), 4.44-4.52 (lH, d, J=12.0Hz, OCH~IAr), 7.28-7.64 (lOH, m, ArH), 7.68 (lH, s, ArH), 8.08-8.18 (2H, m, ArH); MS ~CI~) m/z 562 (M~+1).

.

wo 93~2~181 ~ ~ 3 ~7 ~) r~ r) Pcr/GE~93/oo788 3-r~(2~*.3R*~-((3~5-Bis(trifluoromethvl),~hen~
methvlg~l~e~l~eridino~methvll-5-thiome~h~L~
triazole hvd~ 21Q~l~

Sodium metho~ide (.OOlg) was added to a solution of the compound of E~ample 17 (.lOg) in ethanol (5ml) ~nd the mixture was heated at reflu~ ~or 10 min. Methyl iodide (û.012ml~ in ethanol ~1ml) was added and the mi~ture was heated at reflu~ for 3h. The solvent was then removed in vacuo and 1~he residue was partitioned between e~yl acetate and water. The organic layer was dried (MgSO4) and concentrated in vacuo. The re~idue was p~rified by chromatography on silica 1~ u~g 5û% ethyl acetate in petrol as eluent. The compound was isola$ed as the hydrochloride salt by ~ea'cment of the ~ee base with methanolic hydroge~ chloride: mp 105-107C. lH NMR
(360MH~, DMSO-d6 + TFA) ~ 1.73-1.91 (2H, m, CH2~, 2.05-2.20 (1H, m, CEEI), 2.21-2.3û (lH, m, C~), 2.63 (3H, s, CH3), 3.28 (lH, m, NC;~E[CH2), 3.73 ~lH, m, NCH~CH2), 3.92 (lH, brs, CHO), 4.10 (2H, dd, J=20Hz, 14.5Hz, NCH2), 4.29 (lH, d, J=13Hz, OC~I), 4.68 (lH, ~, CHPh), 4.79 (lH, d, J=13Hz, OCH~), 7.42-7.48 (3~, m, A~H), 7.57 (2H, brs, ArH), 7.88 (2H, s, ArH), 7.95 (lH, s, ArH). MS (CI~ m/z 531 (M~+1, 44%). Found:
C, ~1.29; H, 4.62; N, 9.79; Cl, 6.06. Calcd for C29H24F6N40S.HCl:
C, 50.84; H, 4.44; N9 9.88; Cl, 6.25%.

E~A~PLE 53 6-r{~ Di~hlQr~h~nyl2~çthvloxv)~2~
~h~nvl~i~eridin~methvll-~ !3-di~drQ:~-Qx~L2~-tria~le 2 ~ 3 3 i~ 7 ~

The compound of Descnption 11 was reacted according to the procedure described in Example 35 to af~ord the ~tle compollnd which wa~ recrystallised f~om hot dimethyl~ormamide: mp >220C. lH NMR (360MHz, DMSO-d6, 353K) S 1.45-1.58 (2H, m, CH2), 1.81-1.95 (lH, m, C~H), 2.02-2.12 (lH, m, CH~), 2.18 (lH, dt, J=2.~, 11.5Hz, NC~IEICH2), 2.82 (lH, d, J-14.2Hz, NC~I), 2.94 (lH, brd, NCH~CH2), 3.40 (lH, d, J=14.5Hz, NCHE), 3.45 (lH, d, CHO), 3.52 ~lH, d, CHPh), 3.91 (lE, d, J=12.5Hz, OC~I), 4.34 (lH, d, J=12.5Hz, OCH~, 7.21-7.37 (5H, m, ArH~, 7.47-7.65 (3H, m, ArH).

EXA~IPLE 54 ~-r~(2R*.3R*~3-(~-Carbome,~ho~phenvl~methylo~v~2-~henYll~iperidiIlo~met~diIuum~hlgIide ~e compound of Descrip~on 17 was reacted with 4-picolyl c~loIide according to the procedure described in E~ample 4 to afford the ~ae compound. lH NMR (250MHz, CDCl3) ~ 1.42-1.61 (2H, m, NCH2CH2C~2), 1.98-2.18 (3H, m, NC~IC~2), 2.87-3.04 (2H, m, NC~H-pyridine + NCH~), 3.31-3.39 (lH, m, CHO), 3.48-3.54 (lH, m, NC~h), 3.86 (lH, d, J=14Hz, NCHH-pyridine), 3.93 (3H, s, OCE3), 4.06 (lH, d, J=llHz, OC~r), 4.30 (lH, d, J=11Hz, OC~Ar), 7.12 (lH, m, ArH), 7.22-7.39 (6H, m, ArH), 7.4~-7.56 (2H, dd, pyridiDe-H3, 7.77 (lH, bs, ~ArH), 7.85-7.92 (lH, Ar~I), 8.4~8.55 (2H, dd, pyndine-H). MS (CI~) m/z 417 (M~+1, 50%). Found: C, 64.10; H, 6.06; N, 5.62.
C26H28N2O3.2HCl requires: C, 63.80; H, 6.18; N, 5.72%.

WO 93/21181 2 1 3 ~ ~ 7 rl PCT/GB93/0078X

4-r~(2R*.3R*)-3-((~Çar~oxamidoph~nyl)meth~loxY)-~-Phenylpi~ridino~th~llp~idine The compound of Desmption 1~ was reacted with 4-picolyl chloride according to the procedure described in E: cample 4 to afford ~e ~tle compour~d. lH ~ (360MHz, CDCl3) 1.43-1.56 (2H, m, NCH2CH2CH2~, 2.00-2.17 (3H, m, NC~HC~2), 2.88-3.04 (2H, mj NC~I + NC~HAr), 3.35 (lH, m, CHO), 3.54 (lH, bs, CHPh), 3.83 (lH, d, J=14.5Hz, NC~Ar), 4.08 (lH, d, J_12Hz, OC~HAr), 4.3~ (lH, d, J=12Hz, OC~Ar), 5.6-6.16 (2E, bs, CON~2), 7.11-7.74 (llH, m, ArH), 8.48 (2H, d, J=4Hz, pyridine-H). MS (CI~) mlz 402 (M~+l, 20%).
E~LE ~6 5-r~(2R$.~*)-~-~(2~ th~ -nitl opher~ aethyln~v ~2-phenvl~
The compound of Description 19 was reacted according to the procedure descnbed iri E~ample ~ ord 'che tit~le compound. lE NMR [360MHz, CDCI3~ ~ 1.48-1.64 (2H, m, NCH2CH2C~2), 2.09-2.25 (2~I, m, NCH2Cl~2), 2.37 ~3H, s, C~3), 2.41-2.~;1 (l~I, m, NC~I), 3.12-3.20 (lH, m, NC~I), 3.59 (lH, bB, CEO), 3.64 (lH, bs, C~Ph), 3.73 (lH9 d, J 16Hz, NC~H-het), 3.80 (3H, s, OCE3), 3.91 (lH, d, J=16Hz, NCH~-het), 3.98 (lH, d, J=13Hz, OC~HAr), 4.48 (lH, d, J=13Hz, OCH~Ar), 6.78 (lH, d, J=9Hz, H), 7.22-7.37 (3H, m, ArH), 7.48-7.54 (2H, bd, Ar~), 8.09-8.14 (lH, dd, J=9Hz, J-3Hz, ArH), 8.1~-8.18 (lH, d, J-3Hz, ArH). MS (CI~ ) mlz 439 (M~+l, 100%).

2~ ~337 ~

EXAMPLE~5Z

3-~no-5-r~(~R*.3R*)-3-~inQ-2-methox~h~llYl) methvlo~Y)-~-phenyl~no~methvll- 1 2 .4~oxadiazole The compolLnd of DescTiption 20 was reacted accord~ng to the procedure described in E~ample 1 to af~ord the ti~e compound. ~ NMR (360MHz, CDCl3) ~ 1.41-1.60 (2H, m, NCH2CH2C;~2), 2.13-2.24 (2H, m, NCH2C~2), 2.31 ~lH~ m, NC~), 3.12-3.21 (lH, m9 NCH~), 3.39 (lH, d, J=16Hz, NC~H-het~, 3.47 (lH, m, C~IO), 3.56 (lH, m, NÇ~Ph), 3.61 (3H, s, OC~3), 3.82 (lH, d, J=16Hz, NcEH-Het)~ 4.13 (lH, d, J=13Hz, OC~IAr), 4 34 (lH, d, J=13Hz, OCH~Ar), 5.17 (2H, bs, NE2~
6.38 (lH, bs, ArH~, 6.43-6.48 (lH, m, ArH), 6.54-6.58 (lH, d, 1~ J=8.~Hz, ArH), 7.26-7.68 (3H, m, ArH), 7.48-7.64 (2X, m, ArH).

6-r~(~S.3~aLS~ic(~methvl)~henvl~methvlQ~)-2-~henv~eridin~)methvllur~l The co~pou~ld of Descrip~on 3 was reacted with 6-(chloromethyl)uracil following t~e conditions described in E~ample :4 to afford ~e ~tle compolLnd. lH NMR (3BOMHz, CDCl3) 1.52-1.71 (2H, m, NcH2cH2c~l2)~ 1.99-2.25 (3H, m, NCH~C~ ), 2.69 (lH, d, J=16Hz, NCH~-uracil), 2.92-3.01 (lH, m, NC~l), 3.38-3.40 (lH, m, C~IO), 3.52-3.62 (2H, m, NC~I-UraCi1 + NCEPh), 4.08 (1H, d, J=12HZ, OC~HAr), 4.49 (1H, d, J=12HZ, OCH~IAr), 5.41 11H, S, HA)~ 7.32 7.40 (5H, m, ArH), 7.~0 (2H, S, H~, 7.66 (1H, S, H), 8.64-9.04 (2H, bS, N~ ~ N~E). MS

wo 93/21181 ~ .1 3 3 o 7 7 PCr/GB93/00788 (CI+) m/z 528 (M+l+, 100%). C25H23N3O3F6 requires C, 56.93; H, 4.40; N, 7.97%. Found C, 57.16; H, 4.03; N, 7.88%.

3-rf(2R*~3R*)-~ -Bia~fluQ~Qmçth~hel~Yl~
In~thvlo~v~-2-~2henYl~2eridinQ~methvU-5-~ o~
t~azole The compound of I3escrip~on 1 was reacted with 2-chloro-N-carbo~camidoacetamidhydrazone according to ~e procedure described in E~ample 36 to af~ord the t;itle compound as a white solid: mp 195C. vma3, (KBr) 1680cm-1; Found: C, 55.14; H, 4.58, N, 12.82. Calcd for C~4H23FffN502: C, 54.65, H, 4.40; N, 13.27%.
l~h~

3-rl(2R*~R*)-3-~(3.$-~i~) me~o~:l2h~nvl~i~eri~ Qlm.~th~-cv ~- l .2 ~-tTiazole ~ he compound of Example 59 (0.61g) was dissolYed ir c~loroform (1Oml) a~d the resulting solution was cooled to 0C
in an ice bath. I~iethylamine (2ml) was added followed by phosphorus o~ loride (1.2ml), dropwise. The solulion wa6 25 ~rred at room temperature for lh. The solvent was removed in vacuo and the residue was disper~ed between chloroform alld sodium hydrogen carbonate. The orgaI~ic layer was washed with bnne, dried (MgS04), filtered and concentrated in vacuo. The residue was purified by column chromatography on silica using 30 30% petrol in ethyl acetate as eluent. The product was isolated ?,~ 3~ 7 ~
WO 93/21181 PCl/GB93/00788 ~:' . .
~` - 98 -!.
as the hydrochloride salt using ethereal hydrogen chloride: rnp ~, 81C. MS (Cl+) m/z 610 (M~+1, 60%).

EXAM~I,~l ;~
.~ 3-r(1~;)-1-~(2S.3S~ DichlorQph~nvl)methvlo~v)-2-, _~
L
3 (a) ~-Formvl-2-chlor~ropionamidohvdrazone Sodium metho~ide (.162g) was added to a sollltion of 2-chloropropionitrile (10.5g) in anhydrous methanol (160ml) at 0 C. The reaction mi2~ture was stirred at room temperature for lh, then neutralised with ace~c acid (.18ml). N-3?ormylhydrazine (7.û4g) was added and the mi~ture was stirred overnight. The resul~ng pink solution was concentrated in vacuo to give the title compo~nd as a pink so~id. .
(b) The compound OI Descrip~on 11 (5.9g~ was dissolved in dime~hylformamide (46ml) and N-formyl-2-chloropropionamidohydrazo~a ~3.5g) was added, followed by potasslum carbonate (5.7g). The ~e was stirred at room temperature for 2h, then diluted with ~ylene (150ml) and heated at reflu~ for 2h. When cool, the mixture was filtered and coIlcentrated in vacuo to afford a brown residue. Crude lH NMP~
indicated a ~e of dias~ereoisomers irl 3:1 ~a~o. The residue was purified by medium pressure chromatography (Lo~ar) on silica us~g 4% methanol in di~oromethane as eluent. The first product eluted, diastereoisomer 1, was isolated as a foam which was recrystallised fi~om ether-hexaIle: mp 105-107C lH NMR
(360MHz, CDCl3) ~ 1.31 (3H, d, J=7.0Hz, -CHC~I3), 1.52-1.59 (2H, m, NCH2C~EIC~H), 2.02-2.05 (lH, m, NCH2C~), 2.05-2.16 (1H, m, NcH2cH2c~I)~ 2.51 (lH, t, J=11.5Hz, NC~EI), J 3 ~ .J ~

2.62 (lH, m, NCH~), 3.~6 (lH, s, CHO), 3.77 (lH, s, CHPh), 3.99 (lH, d, J=12.0Hz, QC~I), 4.22 (1H, q, J=7.0Hz, -CE~CH3), 4.30 (lH, d, J_12.0~z, OCH~), 6.89 (2H, d, J=2.0Hz, ArH), 7.21 (lH, t, J=2.0Hz, ArH), 7.3-7.4 ~3H, m, Ar~l), 7.40-7.47 (2H, m, ArH), 7.89 (lH, s, tnazole-2H). MS (CI+) m/z.

,~XAM~

3-r(1R)-1-~2S ~ 2j~loronhenvl~me~h~lo~v)-2-phenvl~ eridino~eth~l~.2~4-triazole - -The second product isolated from the column desc~bed in E~ample 61 was recrystallised fiom ether to af~ord the t;itle compound whose stereoch~mistry was established f~om lH NMR
~.O.e. e~cperiments: mp 132-134C lH NMR (360MHz, DMSO-d6) : ~ ~ 1.06-1.15 ~(lH, m, NCH2C~I2C3~H?, 1.35 (3H, d, J=7.0Hz, CHG~3;3), 1.34-1.42 (lH, m, NCH2C~I), 1.66-1.85 ~2H, m, NC~ICH~), 1.98-2.02 (lH, m, NCH2CH2CH~), 3.01-3.03 (lH, d, J=10.5~Iz, NC~I), 3.39 (lH, s, CHO), 3.86 (lX, d, J-13.0Hz, OC~H), 3.98 (1H, q, J=7Hz, C~CH3)? 4.33 (lH, d, J=13.0Hz, OCH~), 6.92 (lH, d, J=2.0Hz, ArH), 7.26-7.46 (6H, m, ArH, 3-r~(2S.3S)-~-((2.3-Di~thvlnhenyl)methvlo~y~
phenvlpi~eridinnl~e~hvll-1.2.~azQI

Following the method described in Example 16, tlle compound of Description 23 (lOOmg) was reacted with 69mg of N-formyl-2-chloroacetamidohydrazone, to give the til~le compound. lH NMR (CDCl3) ~ 1.50 (2H, m), 1.94 (3H, s), 2.0-3' ~ 7 ~ ``
WO 93/211Xl PCI/GB93/00788 2.3~ (3H, m), 2.2 (3H, s), 3.02 (lH, m), 3.45 (2H, m)9 3.~7 (lH, s~, 3.95 (lH, br s), 3.95 (lH, d, J=llHz), 4.26 (lH, d, J=llHz), 6.86 (lH, d, J=7Hz), 7.06 (lH, d, J=7Hz), 7.2-7.~ (~H, m), 7.7 (lH, br s).

The following compoullds were prepared by the procedure described in Egample 35.

F,X~L~
5-r((2s.3sl:~-((2~3-Dim~thylpkenvl~m~thvloxv)-2 phenylp~ridino~meth~ 2~3-dihydro-~4~-3-oxQ-1~2.4-triazol~

The compolmd of Description 23 was used as starti~g 16 material. lH NMR (CDCl3) ~ 1.4-1.55 (2H, m), 1.89 (3H, s), 1.9-2.2 (3H, m), 2.15 (3H, s), 2.91 (lH, d, J=15Hz), 2.96 (lH, m)~
3.28 (lH, s), 3.50 (lH, s), 3.66 (lH, d, J=15Hz), 4.06 (lH, d, J-12Hz), 4.29 (lH, d, J=12Hz), 6.77 (lH, d, J=7Hz), 6.9 (lH, t, J=7Hz), 6.97 (lH, d, J=7Hz~, 7.2-7.45 (~H, m).
EXA~PLE 65 me~vlo~r)~i~ridino~thyll-3-~Q-1~4-triazgl~
The compound of Des~iptio~ 21 was used as 8tarting material. lH NMR (CDCl3) ~ 1.5 (2H, m), 1.9-2.2 (3H, m), 2.91 (lH, d, 3=15Hz), 3.0 (lH, m), 3.3 (lH, s), 3.6 (lH, s), 3.64 (lH, d, J=15Hz), 4.12 (lH, d, J=12Hz), 4.41 (lH, d, J=12Hz), 7.0-7.45 (9H, m), 9.9 (~H, br 8).

f 7 r~
WO 93/211~1 PCI/C~B93/00788 5-r~(2S.3S)-3 ((3~4-Dichl~{~b~oxv2 phenYl~ip~ridino~meth~-11-3-~xo-1 2~4-tr~azQle The compound of Descrip~on 22 was used as st~ing mateIial. lH NMR (CDC13) ~ 1.5 (2H, m), 1.85-2.2 (3H, m), 2.88 (lH, d, J=15Hz), 3.0 (lH, m), 3.27 (lH, s), 3.48 (lH, s), 3.67 (lH9 d, J=15Hz), 4.05 (lH, d, J=12Hz)) 4.35 (lH, d, J=12Hz), 6.7 (1H, br d, J=7Hz); 6.96 (lH, br s), 7.16 (lH, d, J=7Hz), 7.2-7.45 (5H, m), 9.8 (lH, br s), 10.5 (lX, br s).

EXAMPLE~ç7 1~

Ihe compound of Descript;ion 24 was used as star~g material. lH N~ (CDCl3) ~ 1.23 (9H, s, C(CH3~3), 1.40-1.51 (2H, m, CE2), 1.82-1.85 (lH, m, C~H~, 2.01-2.14 (2H9 m, CH~
and NC~I), 2.74 (lH, d, J=14Hz, NC~H-tnazolone), 2.88 (lH, m, NCH~I.), 3.38 (lH, d, J=14Hz, NCH~-triazolone), 3.ao (lH, m, NCHC~IO), 3.51 ~lH, s, NC~CH0), 3.85 (lH, d, J_12Hz, OC~I), 4.23 (lH, d, J=12Hz, OCE~), 6.80-6.82 (lH, m, ArH), 7.06-7.34 (6H, m, ArH), 7.53-7.55 (2H, m, ArH), 11.16 (lH, s, , P~I), 11.24 (lH, s, NH); MS (CI~) m/z 420 (M++1, 10%). Found:
C, 71.51; H, 7.51; N, 13.08. Cacld. for C25H~2N4O: C, 71.40; H, 7.67; N, 13.32%.

cJ ~? ~J "
WO 93/21181 PCr/C; B93/00788 ~L~ .

5-ri(2R*~3~)-3-((3~ ime~lph~yl)me~h~ylo~sr~-2-~henvlpipendino~m~hyll-3-oxo-1~.4-tria~le The compourld of Description 25 was used as starting m~terial lH NMR (360MHz, DMSO-d6) ~ 1.41-1.47 (2H, m, C~2), 1.81-1.85 (lH, m, C~I), 2.05-2.11 (2H, m, CX~ and NCEH), 2.15 (6H, s, CH3), 2.72 (lH, d, J_14Hz, NC~-triazolone), 2.86-2.89 ~lH, m, NGH~), 3.36 (lH, d, J=2.5Hz, CHO), 3.40 (1H, d, J=14Hz, NCH~-triazolone), 3.44 (lH, brs, CHPh), 3.82 (lH, d, J=12Hz, OC~I~, 4.20 (lH, d, J=12Hz, ~CH~), 6.50 (2H, s, ArH), 6.79 (lH, s, ArH), 7.25-7.33 (3H, m, ArH), 7.~1-7.53 (2H, m, ArH), 11.16 (lH, s, NH), 11.26 (lH, ~, NH~.

~LE~

(2S.3 is(trifluoromet~.henvl)me~hvlo~Y):~-~L~

1-Hydroxybenzotriazole hydrate (308mg), 1-(3-~ethylaminopropyl)-3-ethylcarbodimide hydrochloride (436mg), l~iethylamine (0.3ml) and 1,2,~t~azole-3-caxboxylic acid (129mg) were di~solved in dimethylformamide (5ml) and ~he resulting mixture wa6 stirred for 15 miIl. The compou~d of Desc~ption 3 (0.5g) was added and the resulting mi~ture was stirred at room temperature for 12h. The reaction mi~ture was diluted ~nth water (1OOml) and ~e product was extracted into ethyl acetate (3 ~ 50ml). The organic ~actions were washed WO 93~21181 ~ 1 3 3 7 7 PCI/GB93/00788 success*ely with citric acid (aqueous), water, potassium car~onate and brine, then dried (MgSO4) filtered and concentrated. The residue was p~fied by column chromatography on silica using 70% ethyl acetate in hexane as eluant. The product was recrystallised fi om ethyl acetate/petrol to af~ord a cr~stalline white solid: mp 77-79C. MS (~I-) m/z 478 ((M-HF~, 100%).

EX~PLE IQ
(2$.3~ ~.~is(~T if luQ~Qmeth~vl)phenvl)methvlo~x-1-(1-o~o 2-pvri~4-~l)ethvl-2 I~kenvlpiperidini~n hYdrQchlori~e The compound of Description 3 was reacted with 4-1~ pyridylacetic acid follo~ng the procedure outlined in E~ample 69. This ~orded a colourless oil which was t~eated with ethereal hydrogen chloride and ~e solid obtained was recrystallised from be~ene/he~ane. MS (CI~) mJz 523 (M~
100%). Foulld: C, 64.67, H, 4.86; N, 4.66; Cl, 6.16. Calcd. for Cz7H24F6N2O2-2H2O: G, 54.50; H, 4.91; N, 4.70; Cl, 5.96~o.

(2S~30~ 5-Bi~(~Qm~l)~h~n~l~m~thYlo~z-l-25 (2-ogo-2-~ eth3d~Dheny]~i~eridir~

3-(Bromoacetyl)pyridiniuIn hydrobromide (336mg) was dissolved in dimethylformamide (3ml) and to this solution was added the compound of Description 3 (440mg) followed by 30 potassium carbonate (5~0mg). The mi~ture was stirred at room temperature for 2h, diluted with water and extracted into ethyl 2 ~ ~ ~ fJ 7 ~) wo 93/21181 Pcr/GBg3/oo788 acetate. The organic phase was wa~hed with brine, dried (MgSO4) and evaporated. The residue was purified by chromatography on silica using 70% ether in hexane as eluant and filrther purified b~r medium pressure chromatography 5 (Lobar, using ethyl acetate in hegane (60:40) as eluant. 'H NMR
(2~0MHz, DMSO-d6) ~1.4-1.6 (2H, m), 1.8-1.98 (lH, m, C~I), 2.06-2.2 (l H, m, C H ~I), 2.5-2.6 (l H, m), 2.9-3.0 (l H, m), 3.54 (l H, d, N C~H C 0), 3.62 (l H, brs, C H 0), 3.74 (l H, d, C H P h), 3.84 (l H, d, O C H ~), 7.2-7.3 (2 H, m, ~rH), 7.38-7.~ (3 H, m, f~rH), 7.5 (l H, dd, pyr-H), 7.85 (2 H, s, ~r~l), 7.92 (l H, s, ~rH), 8.14 (l H, dt, pyr-H), 8.62 (l H, dd, pyr-H), 8.94 (l H, d, pyr-H).

El;AIVn?L E 72 3-r(lS)-1-~(2S.~SL~-~(3.5-Bi~(t ifluorom~thvlphenvl) 1~ methvlo~)-~ ~henvl~i~eridinQl~thvll-1.2.4-tria2~1e Thi8 was prepared ~om the compound of Descrip~on 3 and N-formyl-2-chloropropionamidohydrazone following the procedure descnbed in E~cample 61. The first compound to be ~: eluted ~om th~ column (using 3% methanol in dichloromethane 20 as elua~t OD silica) was isolated and characterised as the title compou~d: mp 66-68C. MS (CI~) m/z 499 ((M+1)+, 100%).

E~AMPLE 7~
, 3-r(lR~l-f(2~;~)-3-~3~5-Bis(trifl~aQromethv!)phe-n-vl2 2~ methvlo~:~-p~vlpiperidino~e~vll-1~ riazole The second product isolated f~om the column described in E2cample 72 was rec~y~tallised ~om ethyl acetate~e~a~e to 2 ~ 33077 - 10~ -af~ord ~he tit1e compound: mp 108-111C. MS (CI+) mlz 499 ((M+1)+, 100%).

.~

s-r(~ - ~ ~enYl) ~ethYlo~r)-2-phenylnip~dino~e~hvll-2.3-dihvdro-~:o~Q-L2~4-triazole This compouIld was prepared according to the procedure described in Example 35 using the cornpound of Descnp~on 3 10 and N-carbometho~y-2-chloropropionamidohydrazoIle (ClCH(GH3)C(=NH)NHNHCOOCH3) as star~ing materials. 1H
NMR (CDCl3) ~ 0.94 (3H, d, J=7Hz), 1.4-1.58 (2H, m), 1.8 ~lH, mc), 2.06-2.2 (lH, m)~ 2.26-2.4 (lH, m), 3.3 (lH, mc), 3.52 (lH, s), 3.64-3.72 (2H, m), 4.06 ~lH, d, J=12Hz), 464 (lH, d, J=12Hz), 7.2-7.38 (3H, m), 7.6-7.7 (2H, m), 7.74 (2H, s), 7.94 (lH, s). MS (CI~) m/z 515 ((M+1)+, 23~o).

E~LE 7~
3-~((2S.~i)~-~-Dichl~rophen~)m~tbvloxv~-2-20 ~henvlpio~ ~l}L2.4-~azs le Thi~ was prepared ~om the compound of Descr~p~on 11 according to the procedure described ill E2ample 16 to afford the tit~e compound: mp 208-212C. MS (CI~ mlz 417 ((M+1)+, 100%).
2~

`213 3 ~ "
wo 93/21181 Pcr/G~93/00788 `:

El~AMPLE 76 ~[~(2R*.3~*~-3-((3 .6-~is(tri~wrorn~hv!)phenYl)methvlo~-~-(3-chloro~henvl)~ eridir~1methvll-2.3-dihydro-(4H)-3-s2~o-1~4-triazole This was prepared firom the compound of Descrip~on 26 according to t;he procedure descri~ed in E~ample 36: mp 125-127C. lH NMR (360MHz, DMSO3 ~ I.46-1.52 (2H, m3, 1.9-1.95 (lH, m), 2.0-2.2 (2H, m) 2.92 (lH, d, J=15Hz, NC~ iazolone), 2.98 (lH, mc), 3.35 (lH, s, CHO3, 3.44 (lH, d, J=15Hz, NCH~triazolone), 3.50 (lH, brs, CHPh), 3.96 (lH, d, J=12Hz, OC~H), 4.43 (lH, d, J=12Hz, OCH~), 7.15-7.22 (2H, m, ArH), 7.37-7.41 (2H, m, Ar~I), 7.48 (2H, s, ArH), 7.65 (lH, s, ArH~. MS
(CI+) m/z 536, 537 ~M++1, 100, 30%3.

:E~

5-r~(2&3~3-((3.4-DimethYlphenvl)meth~lo~v)-2-~: phenvl~i~eridi~lmethvll-2.3-dihvdro-(4~)-3-oxo-1.2~4-~ri~ole ~-~ This compound ~was prepared according to the procedure described in Example 35 using the compound of Des~ription 29 20 ~ as 8tarting~material. lH NMR (GDCI3) ~ 1.37-1.55 (2H, m), 1.9-2.2 (3H, m~, 2.1~ (3H, s~, 2.15 (3H, s), 2.&5 (lH, d, J=15Hz), 2.97 (1~, m), 3.26 (lH, s), 3.51 (lH, s), 3.65 (lH, d, J=15Hz), 4.06 (1HJ d, J=llHz), 4.26 (lH, d, J=llHz),6.65 (2H, m), 6.9 (lH, d, J-8Hz), 7.2-7.45 (5H, m), 9.5 (lH, brs).
~XAMPLE 78 : ~ 5-rlt2S.3S~3-((3-iPropo~mhenvl)methYloxv)~-~nvlDipe~idino~thvll-2.3-dihvdro-~-3-Q~-1.2~-triazol~

wO 93/21l81 ~ !,J r~J ~l PCI/GB93/00788 This compound was prepared according to the procedure descnbed in Example 35 using the compound of Description 30 as star~ng m^~terial~ lH NMR (Cl:)Cl3) ~ 1.25 (6H, d, J=6Hz), 1.35-1.55 (2H, m), 1.9-2.2 (3H, m~, 2.89 (1H, d, J=15Hz), 2.99 (lH, d, J=lOHz), 3.27 (lH, s), 3.51 (lH, s), 3.66 (lH, d, J=15Hz), 4.1 (lH, d, J=12Hz), 4.38 (lH, m), 6.48 (lH, d, J=7Hz), 6.~7 (lH, s), 6.66 (lH, d, J=7Hz), 7.2-7.5 (5H, m).
E~AMPIIE 7~

5-r~(2S.3S~3-(t3-FluQro-5-methyl~henvl)methvlQxy):2-phenvl~il)e~idino~methvll-2~-dihYdro-(4H)-3-~xo-1.2.4-triazole This was prepared by the reaction of the compound of Description 27 according to the procedure outlined in Example 35: mp 228-229G. lH NMR (360MHz? DMSO) ~ 1.4-1.55 (2H, m, CH2), 1.8-I.9 (1~I, m, CH2), 2.02-2.18 (2H, m, CH2 and NCH~), 1~ 2.21 ~3H, s, GH3), 2.73 (lH, d, N~H~-het, J=14Hz), 2.87-2.90 (lH, d, NC~I, J=llHz), 3.32-3.40 (lH, m, NCHCHO), 3.41 (lH, :; d, N(~-het, J=14Hz), 3.46 (lH, s, NCHCHO), 3.87 (lH, d, OCHI~-Ar, J=12.~iHz), 428 (lH, d, OCH~-Ar, J=12.5Hz), 6.50-6.55 (2H, m, ArH), 6.80-6.83 (lH, m, ArH), 7.29-7.31 (3H, m, ArH)9- 7.51-7.~3 (2H, m, ArH), 11.18 (lH, s, NH), 11.28 (lH, s, NH~. MS (CI~) m/z 397 (M~+1, 10%).
-EXAMPLE ~Q

5-r~3-(3R*)~((3.5-~is(trifluoromethyl2~henYl)~xleth~10~2-m~yl-a-(2R*~-phenvl~ineridinQ~meth~ll-2~3-dihvdro-(4~-3 ~x~1 .2.4-tliaznle Thi8 was prepared from the compolmd of Description 28 according to l~he procedure ou~ined in E~ample 35. lH NMR

2 13 ~"J 7 ~
WO 93/21181 P~/GB93/00788 : -(360MHz, MeOD) ~1.43 (3H, s, CH3), 1.46 (1H~ m), 1.91 (3H, m), 2.67 (2H, m), 2.98 (lH, d, J=1~Hz, NCHHtriazolone), 3.21 (2H, m), 3.68 (lH, d, J=15Hz, NCH~ triazolone), 3.72 (lH, d, J=12Hz, OC~I), 4.36 (lH, d,-J=12Hz, (:)CHO, 7.18 (lH, t, ArH),- 7.25 (2H, t, ArH), 7.37 (2H, s, ArH), 7.53 (lH, s, ArH), 7.56 (lH, s, ArH), 7.71 (lH, s, ArH).

E~AMPLE ~1 s-r~(2s 3S)-3-((3.5-Bis(trifluoromethYl)phenvl)methYlo~-2-(3-fluoroph~nvl)piperidino~methvll2 ~3-dihvdro-(4H)-3-o~o-1 .~:
triazole lH NMR (CDCl33 ~ 1.42-1.62 (2H, m), 1.84-2.2 (3H, m), 2.86-3.1 (2H, m), 3.38-3.58 (3H, m), 4.08 (lH, d, J=12Hz, OCH~), 4.54 (lH, d, J=12Hz, OC;EI), 6.92-7.04 (lH, m, ArH), 7.16-7.32 (3H, m, ArH), 7.54 (2H, s, ArH), 7.76 (~H, s, ArH).

3-rS(2S 3S)-3-((3.5-Bis(tri~uoromethvl)phenvl)~çthvlo~y)-2-henvl~i~eridinQ~m~thvll-1 .2.4-tria~
(a~ The compound of Description 3 (lg) was dissolved in dimethylformamide (8ml) and N-t-butylo~ycarbonyl-2-chloroace~idrazone (0.6g3 was added, followed by potassium carbonate (0.9g). The mi~ture was sti2~ed at room temperature dver~ight. The mi2~ture was diluted with water, e~tracted with ethyl acetate and ~e organic layer was washed with brine, dried (MgSO4) and evaporated. The residue was purified by column chromatography on silica using ethyl acetate as eluant.
This afforded the compound as a white solid which was WO 93/21181 213 ~ 0 7 ~ PCr/GB93/00788 recrystallised f~om ether^hexane. lH NMR (360MHz, CDCl3) 1.40 (9H, s, (CH3)3)t 1.42-1.6 (3H, m), 2.13-2.2 (2H, m), 2.62 (lH, d, J=16Hz, NCE3I(:=NH), 3.07-3.10 (lH, m, C~IN), 3.36 (lH, d, J=15Hz, NC~C=NH), 3.38 ~lH, s, CHO), 3.~7 (lH, brs, C~IPh), 4.Q2 (lH, d, J=12Hz, OC~H), 4.45 (lH, d, J=12Hz, OG~, 7.25-7.40 (5H, m, ArH), 7.53 (2H, s, ArH3, 7.73 (1H, s, ArH).
(b) The Boc-protected amidrazone (lg) was dissolved in methanolic hydrogen chloride and s~rred for 12h. The solvent 10 was evaporated and the cruds product was used in subsequent reactions without further purification.
(c) The amidrazone hydrochlo~ide of (b) above (200mg) was dissolved in ethanol (2ml). Mag~esium sulphate was added (lOOmg) and the mi~ture stirred for 30min. Triethylamine 1~ (0.06ml) was added followed by glyoxal (9Omg, trimenc dihydrate). This misture was allowed to stir for 12h. The solve~t was removed in vacuo and the residue was dispersed between ethyl acetate and water. The organic layer was dried (MgSQ4) and concentrated to afford a brown oil. This was purified by 20 colu~n chromatography on silica using hexane in ethyl acetate (95%) to afford the ti~e compolmd. lH NMR (360MHz, CDCl3) 1.53-1.72 (2H, m, CH2), 1.98-2.22 (2H, m, CH23, 2.42-2.~3 (lH, m, NC~H), 3.14-3.22 (lH, m, NCH~), 3.61 (lH, bs, CHO), 3.74-3.81 (2H, m, NCEPh + OC~I), 4.04 (lH, d, J=12Hz, 2~ NC~Htriazine), 4.19 (lH, d, J=12Hz, OCH~), 4.47 (lH, d, J=12Hz, NCHHtriazine), 7.24-7.37 (4H, m, ArH), 7.48 7.6 (4H, m, ArH), 7.70 (lH, s, ArH), 8.6 (lH, s, ArH). MS (CI+) m/z 497 (M~+1, 100%).

~ 1 ~ o 7 rl PCT/GB93/007B8 The following examples illustrate pharmaceutical compositions according to the invention.

E~AMPLE 83A Tablets contai.ninq 1-25mq of comPound Amount mq Compound of formula (I) l.O 2.O 25.0 Microcrystalline cellulose 20.0 20.020.O
Modified food corn starch 20.0 20~020.0 Lactose 58O5 57.534.5 Magnesium Stearate . 0.5 O.5 O.5 EXAMPLE 83B Tablets_containin~ 26-lOOm~ of compound Amount mq Compound of formula (I) 26.0 50.0 lOO.O
Microcrystalline cellulose80.0 80.0 80.0 Modified food corn starch80.0 80.0 80.0 Lactose 213.5 1~9.5 139.5 Magnes-ium Stearate O.5 O.S 0.5 The compound of formula ~I), 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 s~arch and the magnesium stearate. The resulting granulation is then compressed into tablets containing l.Omg! 2~Omg, 25.Omg, 2~.Omg, 50.Omg and lOOmg of the active compound per tablet.

Parentexal in~_ction Amount m~
Compound of formula (I~ 1 to lOOmg Citric Acid Monohydrate 0.75mg Sodium Pho5phate 4.Smg Sodium Chloride 9mg Water for Injections to lml WO93/21181 2 ~ `) 7 ~1 PCT/GB93/00788 The sodium phosphate, citric acid monohydrate and sodium chloride are dissolved in a portion of the water. The compound of fonmula (I) is dissolved or suspended in the solution and made up to volume.

EXAMPLE 85 Topical~f3:aYLL~.D
Amount mq Compound of formula (I) l-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 compo~nd of formula ~I) is added and stirring continued until dispersed. The mixture is then cooled until solid.

, ,

Claims (35)

CLAIMS:
1. 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;
R1 represents phenyl optionally substituted by 1, 2 or 3 groups selected from C1-6alkyl, C2-6 alkenyl, C2-6alkynyl, halo, cyano, nitro, trifluoromethyl, trimethylsilyl, -ORa, SRa, SORa, SO2Ra, -NRaRb , -NRaCORb NRaCO2Rb, -CO2Ra or -CONRaRb;
R2 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 C1-6alkyl, C1-6alkoxy, halo or trifluoromethyl;
R4 and R5 may be present on any available carbon atom of the azacyclic ring and each independently represent H, halo, C1-6alkyl, oxo, CH2ORa, CO2Ra or CONRaRb;
R8 represents an optionally substituted aromatic heterocycle; and Ra and Rb each independently represent H, trifluoromethyl, C1-6alkyl or phenyl optionally substituted by C1-6alkyl, 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 (CH2)n may be substituted by R12 and/or R13;
X represents O or S;
R10 represents phenyl optionally substituted by 1, 2 or 3 groups selected from C1-6alkyl, C2-6 alkenyl, C2-6alkynyl, halo, cyano, nitro, trifluoromethyl, trimethylsilyl, -ORc, SRc, SORc, SO2Rc, -NRcRd, -NRcCORd, -NRcCO2Rd, -CO2Rc or -CONRcRd;
R11 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 C1-6alkyl, C1-6alkoxy, halo or trifluoromethyl;

R12 and R13 each independently represent H, halo, C1-6alkyl, oxo, CO2Rc or CONRcRd;
R14 represents C1-4alkyl, optionally substituted by oxo, substituted by an optionally substituted aromatic heterocycle; and Rc and Rd each independently represent H, C1-6alkyl, phenyl optionally substituted by C1-6alkyl, halo or trifluoromethyl;
or a salt or prodrug thereof.
3. A compound as claimed in claim 2 wherein n is 2 or 3; R12 and R13 each independently represent H, halo, C1-6alkyl, CO2Rc or CONRcRd; R14 represents C1-4alkyl substituted by an optionally substituted 5- or 6-membered aromatic heterocycle; and Rc and Rd each independently represent H, C1-6alkyl, phenyl or trifluoromethyl.
4. A compound as claimed in any preceding claim wherein R1 represents phenyl substituted by one or more groups selected from C1-4alkyl, trifluoromethyl and halo.
5. A compound as claimed in any preceding claim wherein R2 represents benzhydryl or optionally substituted phenyl.
6. A compound as claimed in any preceding claim wherein R8 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 R8 represents a substituted or unsubstituted 5- or 6-membered nitrogen-containing aromatic heterocycle.
8. A compound as claimed in claim 7 wherein R8 represents optionally subskituted oxazolyl, oxadiazolyl, imidazolyl, thiadiazolyl, triazolyl, pyrazinyl, pyrimidinyl, pyridazinyl or triazinyl, or tetrazolyl substituted by C1-6alkyl.
9. A compound as claimed in claim 8 wherein R8 represents unsubstituted triazolyl 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-1,2,4-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-[((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-[((2R*,3R*)-3-((3,5-bis(trifluoromethyl)phenyl) methyloxy)-2-phenylpiperidino)methyl]-3-bromo-1,2,4-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-1-(2-thienoyl)piperidine;
(2R*,3R*)-3-((3,5-bis(trifluoromethyl)phenyl)methyloxy)-2-phenyl-1-(2-thienyl)methylpiperidine;
5-[((2R*,3R*)-3-((3,5-bis(trifluoromethyl)phenyl) methyloxy)-2-phenylpiperidino)methyl]-2,3-dihydro-4-methyl-3-thioxo-1,2,4-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)methyloxy3-2-phenylpiperidino)methyl]-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-[((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-[((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-(p-toluenesulphonyl)imidazole;
2-[((2S,3S)-3-((3,5-bis(trifluoromethyl)phenyl) methyloxy)-2-phenylpiperidino)methyl]imidazole;
4-[((2S,3S)-3-((3,5 bis(trifluoromethyl)phenyl) methyloxy)-2-phenylpiperidino)methyl]imidazole;
5-[((2R*,3R*)-3-((3,5-bis(trifluoromethyl)phenyl) methyloxy)-2-phenylpiperidino)methyl]-2,3-dihydro-(4H)-3-oxo-1,2,4-triazole;
5-[((2R*,3R*)-3-(3,5-bis(trifluoromethyl)phenyl) methyloxy)-2-phenylpiperidino)methyl]-3-(N,N-dimethylamino)-1,2,4-thiadiazole;
5-[((2S,3S)-3-((3,5-bis(trifluoromethyl)phenyl) methyloxy)-2-phenylpiperidino)methyl]tetrazole;
5-[((25,3S)-3-((3,5-bis(trifluoromethyl)phenyl) methyloxy)-2-phenylpiperidino)methyl]-2-methyltetrazole;
5-[((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-1,2,4-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-diphenylmethyl)pyrrolidino)methyl]-2,3-dihydro-(4H)-3-oxo-1,2,4-triazole;

5-[((2R,3S)-3-((3,5-bis(trifluoromethyl) phenyl)methyloxy)-2-diphenylmethyl)pyrrolidino)methyl]-2,3-dihydro-(4H)-3-oxo-1,2,4-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)methyl]-2,3-dihydro-(4H)-3-oxo-1,2,4-triazole;
5-[((2S,3S)-3-((3,5-bistrifluoromethyl)phenyl)methyloxy)-2-phenylpiperidino)methyl]-2,3-dihydro-(4H)-3-oxo-1,2,4-triazole;
3-[((2S,3S)-3-((3,5-bistrifluoromethyl)phenyl)methyloxy)-2-phenylpiperidino)methyl]-1-methyl-1,2,4-triazole;
3-[((2S,3S)-3-((3,5-bistrifluoromethyl)phenyl)methyloxy) 2-phenylpiperidino)methyl]-5-phenyl-1,2,4-oxadiazole;
3-[((2R*,3R*)-3-((3,5-bistrifluoromethyl)phenyl) methyloxy)-2-phenylpiperidino)methyl]-5-thiomethyl-1,2,4-triazole;
5-[((2S,3S)-3-((3,5-dichlorophenyl)methyloxy)-2-phenylpiperidino)methyl-2,3-dihydro-(4H)-3-oxo-1,2,4-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-1,2,4-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-[(1S)-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-1,2,4-triazole;
5-[((2S,3S)-2-phenyl-3-((3-trifluoromethyl)phenyl) methyloxy)piperidino)methyl]-2,3-dihydro-(4H)-3-oxo-1,2,4-triazole;
5-[((2S,3S)-3-((3,4-dichlorophenyl)methyloxy)-2-phenylpiperidino)methyl]-2,3-dihydro-(4H)-3-oxo-1,2,4-triazole;
5-[(2S,3S)-3-((3-t-butylphenyl)methyloxy)-2-phenylpiperidino)methyl]-2,3-dihydro-(4H)-3-oxo-1,2,4-triazole;
5-[((2R*,3R*)-3-((3,5-dimethylphenyl)methyloxy)-2-phenylpiperidino)methyl]-2,3-dihydro-(4H)-3-oxo-1,2,4-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-(1-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-(1S)-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-(1S)-1-((2S,3S)-3-((3,5-bis(trifluoromethyl)phenyl) methyloxy)-2-phenylpiperidino)ethyl]-2,3-dihydro-(4H)-3-oxo-1,2,4-triazole;
3-[((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-1,2,4-triazole;
5-[((2S,3S)-3-((3,4-dimethylphenyl)methyloxy)-2-phenylpiperidino)methyl]-2,3-dihydro-(4H)-3-oxo-1,2,4-triazole;
5-[((2S,3S)-3-((3-i-propoxyphenyl)methyloxy)-2-phenylpiperidino)methyl]-2,3-dihydro-(4H)-3-oxo-1,2,4-triazole;
5-[((2S,3S)-3-((3-fluoro-5-methylphenyl)methyloxy)-2-phenylpiperidino)methyl]-2,3-dihydro-(4H)-3-oxo-1,2,4-triazole;
5-[(3-(3R*)-((3,5-bis(trifluoromethyl)phenyl)methyloxy)-2-methyl-2-(2R*)-phenylpiperidino)methyl-2,3-dihydro-(4H)-3-oxo-1,2,4-triazole:
5-[((2S,3S)-3-((3,5-bis(trifluoromethyl)phenyl) methyloxy)-2-(3-fluorophenyl)piperidino)methyl]-2,3-dihydro-(4H)-3-oxo-1,2,4-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):

(II) wherein R1, R2, R4, R5, X and n are as defined for formula (I), with a reagent suitable to introduce the group Y-R8; or (B) reacting a compound of formula (III) with a compound of formula (IV):

(III) (IV) wherein R1, R2, R4, R5, X, Y and n are as defined for formula (I), R30 represents an alkyl group and R31 represents H or a suitable substituent, in the presence of a base; or (C) reacting a compound of formula (V):

(V) wherein R1, R2, R4, R5, X, Y and n are as defined for formula (I), with an alkali metal azide; or (D) reacting a compound of formula (VI):

(VI) wherein R1, R2, R4, R5, X, Y and n are as defined for formula (I), with a compound of formula Hal-CH2C(=O)R60, where Hal represents halo and R60 represents H or a suitable substituent; or (E) reacting a compound of formula (VII):

(VII) wherein R1, R2, R4, R5, X, Y and n are as defined for formula (I), with a compound of formula R61NCS, wherein R61 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):

(VIII) wherein Y and Hal are as previously defined and R18 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 R1, R2, R4, R5, 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 R1, R2, R4, R5, X, Y and n are as defined for formula (I) and R35 and R36 each independently represent 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-R8 is R8-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. A process as claimed in claim 12 wherein, for (D), R60 is H or C1-6alkyl.
18. A process as claimed in claim 12 wherein, for (E), the base is 1,8-diazabicyclo[5.4.0]undec-7-ene.
19. A process as claimed in claim 12 wherein, for (F), R18 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), R35 and R36 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. A method 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 arthritic.
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 1 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.
CA002133077A 1992-04-15 1993-04-14 Azacyclic compounds Abandoned CA2133077A1 (en)

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GB929219686A GB9219686D0 (en) 1992-09-17 1992-09-17 Therapeutic agents
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