AP751A

AP751A - Oxa-and thia-diazole muscarinic receptor antagonists.

Info

Publication number: AP751A
Application number: APAP/P/1997/000930A
Authority: AP
Inventors: Alexander Roderick Mackenzie; Anthony Wood; Robert John Bass
Original assignee: Pfizer Res & Development Company N V /S A
Priority date: 1996-02-22
Filing date: 1997-02-20
Publication date: 1999-07-12
Also published as: BR9707733A; BG102699A; HK1018274A1; DE69704701D1; HN1997000020A; HUP9900501A3; PE42798A1; JPH11504051A; BG63971B1; EP0885218A1; GR3036032T3; IL125413A0; AR005916A1; US5977142A; IL125413A; HRP970098B1; ID16642A; TR199801644T2; SK283461B6; RU2162848C2

Abstract

A compound of the formula wherein R1 is d-C6 alkyl, halo-(d-C6 alkyl), C3-C7 cycloalkyl, C2-C6 alkynyl, hydroxy-(C2-C6 alkynyl), (d-C4 alkoxy)-(C2-C6 aikynyl), aryl, aryl-(Ci-C4 Jkyl),heteroary or heteroaryi-(Ci-C4 alkyl); R2 is H or d-C4 alkyl; R3 is aryl, heteroaryl, 2,3-dihydrobenzofuranyl or C4-C7 cycloalkyl; XisOorS; and Y is a direct link, -CH2-, -(CH2)2- or -CH2O-; or a pharmaceutically acceptable salt thereof. fhe compounds are muscarinic receptor antagonists useful in the treatment of, e.g., irritable bowel syndrome and urinary incontinence. The compounds are also useful as cognition enhancers.

Description

This invention relates to substituted oxadiazole and thiadiazole derivatives. The compounds of the invention are muscarinic receptor antagonists which are selective for smooth muscle muscarinic sites over cardiac muscarinic sites and which do not have any significant antihistaminic activity. Thus the compounds are useful in the treatment of diseases associated with altered motility and/or tone of smooth muscle which can, for example, be found in the gut, trachea and bladder. Such diseases include irritable bowel syndrome, diverticular disease, urinary incontinence, oesophageal achalasia and chronic obstructive airways disease.

The compounds are also useful as cognition enhancers, and are thus useful in treating diseases involving memory impairment such as Alzheimer’s disease and age-related memory disorder.

According to the invention there are provided compounds of the formula:-

- (I)

£ 6 0 0 / L 6 /d/dV wherein R¹ is C-i-C₆ alkyl,-haio-(Ci-C₆ alkyl), C3-C7 cycloalkyl, C₂-C₆ alkynyl, hydroxy-(C₂-C₆ alkynyl), (C1-C4 alkoxy)-(C₂-C₆ alkynyl), aryl, aryl-(C₁-C₄alkyl), heteroaryl or heteroaryl-(CrC4 alkyl);

R² is H or C1-C4 alkyl;

R³ is aryl, heteroaryl, 2,3-dihydrobenzofuranyl or C4-C7 cycloalkyl;

X is O or S;

and Y is a direct link, -CH₂-, -(CH₂)₂- or -CH₂O-; and their pharmaceutically acceptable salts.

By halo is meant chloro, bromo, fluoro or iodo.

Preferred aryl groups are phenyl and naphthyl both optionally substituted by up to 3 substituents each independently selected from C1-C4 alkyl, C1-C4 alkoxy, hydroxy, halo and trifluoromethyl.

AP. Ο Ο 7 5 1

More preferably, the aryl groups are selected from phenyl optionally substituted by 1 or 2 substituents each independently selected from Ci-C₄ alkyl, Ci04 alkoxy, hydroxy, halo and trifiuoromethyl; and naphthyl.

Most preferably, the aryl group is phenyl, fluorophenyi, dichlorophenyl, hydroxyphenyl, methoxyphenyl or naphthyl.

Preferred heteroaryl groups are thienyl, pyridyl, thiazolyl, benzothiazolyl,’ thiadiazolyl, pyrazolyl and pyrimidinyl, all optionally substituted by 1 or 2 substituents each independently selected from C1-C4 alkyl, CrC₄ alkoxy, hydroxy and halo.

More preferred heteroaryl groups are thienyl, pyridyl, thiazolyl and benzothiazolyl.

Preferred alkyl groups are methyl and ethyl. Preferred alkoxy groups are methoxy and ethoxy. Preferred halo groups are chloro, bromo and fluoro. Preferred cycloalkyl groups are cyclobutyl, cyclopentyl and cyclohexyl, particularly cyclobutyl. The preferred alkynyl group is ethynyl. Preferred hydroxy -(C₂-C₆ alkynyl) groups are HO-CH₂C=C- and HO-(CH₂)₄-CaC-. The preferred haloalkyl groups are trifiuoromethyl and pentafluoroethyl.

R¹ is preferably C1-C6 alkyl; pentafluoroethyl; C₄-C₆ cycloalkyl; ethynyl; -CsC-CH₂OH; -C=C-(CH₂)₄OH; a phenyl group optionally substituted by 1 or 2 substituents each independently selected from halo, C1-C4 alkyl, Ci-C₄ alkoxy and hydroxy; naphthyl; or a heterocyclic group selected from thienyl, pyridyl, thiazolyl and benzothiazolyl, all optionally substituted by halo, C_rC₄ alkyl, Ci-C₄ alkoxy or hydroxy.

R² is preferably H or CH₃.

R³ is preferably either phenyl optionally substituted by 1 or 2 substituents each independently selected from halo, Ci-C₄ alkyl, Ci-C₄ alkoxy and hydroxy;

2,3-dihydrobenzofuranyl; C.4-C7 cycloalkyl or thienyl.

ΔΡ/Ρ/ 0 7 Ζ Λ η 0 X n

X is preferably 0.

AP. ο Ο 7 5 1

Υ is preferably a direct link, -CH₂- or -CH₂O-.

The pharmaceutically acceptable salts of the compound of formula (I) include acid addition salts such as the hydrochloride, hydrobromide, hydrofluoride, sulphate or bisulphate, phosphate or hydrogen phosphate, acetate, besylate, citrate, fumarate, gluconate, lactate, maleate, mesylate, succinate and tartrate salts. For a more comprehensive list of pharmaceutically acceptable salts see, for example, the Journal of Pharmaceutical Sciences, Vol. 66, No. 1, January 1977, pages 1-19. These salts can be prepared conventionally, e.g. by mixing a solution of the free base and the acid in a suitable solvent, e.g. ethanol, and recovering the acid addition salt either as a precipitate, or by evaporation of the solution.

The compounds (I) may contain one or more optically active centres and the invention includes both the separated and unseparated forms. The separated forms can be obtained by conventional means, e.g. by using high performance liquid chromatography employing a chiral stationary phase, or by chemical resolution via the formation of suitable salts or derivatives.

One method to the compounds (I) is via the ketones (11):02600/Z6 /d/dV

R² where X, Y, R² and R³ are as defined for formula (I), by reaction with a Grignard, organolithium or organocerium reagent of the formula:R¹MgHal, R¹Li or R¹CeCI₂where Hal is Cl or Br, in a suitable organic solvent.

AP. ύ υ 7 5 1

When an organolithium or organocersum reagent is used, the reaction is typically carried out at low temperature, i.e. at 0°C or below, and preferably at about -78°C.

A preferred organic solvent is tetrahydrofuran.

The preferred Grignard reagents are the magnesium bromides.

The Grignard reagents can be generated in situ, e.g. by adding a halide of the formula R¹Hal dropwise to a suspension of magnesium turnings in an organic solvent such as diethyl ether at a rate sufficient to maintain reflux. After stirring for, say, about 30 minutes at room temperature, the resulting solution containing the Grignard reagent is added dropwise to a solution of the ketone (II) in a suitable organic solvent, typically at a temperature of 0° to -20°C.

The product can be isolated from the reaction mixture conventionally.

The novel intermediates (II) also form a part of the invention.

u ΐ o u u / l υ ζα/αν

AP.00751

The intermediates (ii) in which X is O are preparable by conventional techniques, e.g. as follows:CO,H

CONHCH,COPh

Sodium nitrite/HOAc

jjToluenesulfonyloxy, etc.]

O

- (IIA)

CH(R²)—Y-R³ 'COCIT ί 6 0 0 / L 6 /d/dV

AP. Ο ο 7 5 1

An alternative route to the intermediates (IIA) is as follows:(TBDMS = te rt-butyldime thy Is ily 1)

OTBDMS

PhCH(OH)C=\

TBDMS—CI

Imidazole, Mandelo nitrile

-► Ph—CH—C ξΝ (TBDMS = te rt- butv Idime thy Is il γ 1)

Hydroxylamine hydrochloride, K₂CO₃

OTBDMS

o t ΰ υ υ / zb /d/dv

I (HA)

N

CH(R²)—Y-R³

AP.00751

Routes to the thiadiazoie intermediates are as follows;(a) s—N

Cl

N

ΟΊΉΡ

Ph

CO->Me

IN

-Ph ΐ LDA/THF

J.MetLChem.,1990,33,2052 J.Me±Chera,1989,32(1),105

MnO,

ii)HCl/pH2

O

(ΠΒ) (IIC)

-R3

AP/P/ 9 7 / 0 0 9 3 0

THP = Tetrahydropyranyl

AP.00751 or (b)

OTHP

HCl/pH2 „ , Then as (a) above

Compounds (IIB) -«-—— and (IIC) * OH

apzp/ q 7 /nnaxn

AP. Ο Ο 7 5 1

Another method to the compounds (I) is from a hydroxy-containing compound (III) or base salt thereof:-

wherein R¹ and X are as defined for formula (I), either (a) by reaction with a compound of the formula (IV):Q—CH(R²)-Y—R³ - (IV) wherein Q is a leaving group such as tosyloxy, mesyloxy, trifluoromethanesulfonyloxy, Cl or Br and R², R³ and Y are as defined for formula (I); or (b), by reaction with an aldehyde or ketone of the formuia

R³—Y— C— R² - (V)

II o

wherein R², R³ and Y are as defined for formula (I), in the presence of a reducing agent, e.g. sodium triacetoxyborohydride or sodium cyanoborohydride, in a suitable organic solvent, e.g. tetrahydrofuran, and typically at room temperature.

When the free base of compound (III) is used in (a), the reaction is typically carried out in the presence of an acid acceptor such as sodium bicarbonate or ethyldiisopropylamine.

The compounds of the formula (III) can be prepared by removal of the benzyl group from the compounds of the formula (I) in which the group “-CH(R²)-Y-R³” is benzyl, typically by reaction with a suitable chloroformate,

e.g. α-chloroethylchloroformate, in a suitable organic solvent, e.g. dichloromethane or toluene, and preferably under reflux.

The selectivity of the compounds (I) as muscarinic receptor antagonists can be measured as follows.

0E600/Z6 /d/dV

AP. Ο Ο 7 5 1

Male guinea pigs are sacrificed and the ileum, trachea, bladder and right atrium are removed and susoenced in pnvsiclcgical sd- sonnicri under a resuing tension of lg am 32°C aerauec wi_Ln 5:·$ 0, and 5¾ CO,. Contractions of the ileum, bladder and trachea are recorded using an isotonic (ileum) cr isometric transducer (bladder and trachea). The frscuency cf contraction o- ’-he sOonvcnecusly beating right atrium is derived from isometrically recorded contractions .

Dose-response curves to either acetylcholine (ileum) or carbachol (trachea, bladder and right atrium) are determined using a 1-5 minute conuacu time for each dose of agonist until the maximum response is achieved. The organ barn is drainec ano refilled with physiological salt solution containing the lowest dose of the tesu compound. Tne uesu compound is allowed to equilibrate witn the tissue fcr 20 minutes and tne aacnis<- dose—response curve i-S Ό.ΠΪ.ϋ tS-lS IHS-XiinHin 3ToS wCi iS ci is CCudinSCThe organ bath is drained and refilled with physiological salt solution concerning die second concentration cf test compound and tne above procedure is repeated. Typically four concentrations of the res” compound are evaluauso on each tissue.

The concentration cf tne t=s>_ c^niucund wnicn. causes a dcui produce the cri value - Aruni

Pharmacol., 14./ 43-53). Using cue accv = . τ , _T-~~ 4 f f—i icscx Τ’ ' S S ul S SclsC- 3. '/«.<—·/ i. C 2

bling cf	the	agonist	ccncen	tration to
original	resocnsa is	C.S.TL = 272n	ined (pA·,
iakshana	and	Schild	(15=9) ,	C 27 2. Ur · kJ ·

• TTcccnisu.s is cew=mmed.

AP . Ο Ο 7 5 1

Activitv against accnist induced brcnchc-

constriction cr	gut cr bladder contractil	ity in
comparison with	changes in heart rate is	determined
in the anaesthet	ised ccc. Oral activity	is assessed
in the conscious	deg determining compound	effects

cn, for example, hearrats, pupil cic;uSv=r end gut motility.

Compound affinity for other cholinergic sites is assessed in the mouse after either intravenous or intraoeritoneal administration. Thus, die dose which causes a doubling of pupil size is determined as well as the dose which inhibits tne salivation and tremor responses to intravenous exotremorine by 50% .

For administration to man in the curative cr prophylactic treatment of diseases associated with the altered motility and/or tone cr smccon muscle, such as irritable bowel syndrome, diveruiculcr disease, urinary incontinence, cesoph<=.g<=s.l acn<=.lc.sia and chronic obstructive airways disease, oral dosages cf the compounds will generally be in tne range of from 3.5 to 350 mg daily for an average adult patient (70 kg) . Thus for a typical adult patient, individual tablets or capsules will tvoicallv contain from 1 to 2o0 mg or cCvive comoound, in a suitable pharmaceutically eccep^cole vehicle cr carrier for acminis'-ration Sj.i.giy or in multiole coses, once or several cines =. c=y.

Dosaces for intravenous admniscraeion tvoicallv be within the range 0.3Ξ to 3o mg per single dcse as required. In practice the physician will determine the actual ccsage wnicn «ill oe mcs<_ suitable for an individual patie.no and io will vary with the age, weight and response cr i_ne particular patient. The above dosages are exemplary cr tne average case but there can, cr course, be _ncivicue_ instances where higher cr lower dosage ranges era

AP/P/ 9 7 / 0 0 9 3 0

AP .00751 merited, and such are within the scope of this invention.

For human use, the compoundscf the formula (1) can be administered alone, but will generally be administered in admixture with a pharmaceutical carrier selected with regard to' the intended route of administration and standard pharmaceutical practice. For example,they can be administered orally in the form of tablets containing such excipients as starch or lactose, or in capsules or ovules either alone or in admixture with excipients, or in the form of elixirs or suspensions containing flavouring cr colouring agents.They can be injected parenterally, for example, intravenously, intramuscularly or subcutaneously. For parenteral administration,they are mesa usee in i_ne torn of <=. sterile aeneous solution which may contain Other substances, for example, enough. salts or glucose to make the solution isotonic with bleed.

In a further aspect the invention provides a pharmaceutical composition comprising a compound of the formula (I), cr a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable diluent or carrier.

The invention also includes a compound Ct i—;e formula (I) or a pharmaceutically acceptable salt thereof, for use as a medicament, particularly for use in the treatment cf urinary incontinence or irritable bowel syndrome.

The invention further includes tne use or a compound of the formula (i) , or Ot <=. pharmaceutically acceptsole sain t.cer = ot , tor the manufacture cf a medicament fcr tne treatment-or diseases associated with the altered motility and/or tone of smooth muscle, sucn as ccwel syndrome, diverticular disease, unn&rv incontinence, cescphageai acnalssic. dd c..rente t 6 0 0 / L 6 Zd/dV

AP . 0 0 7 5 1 obstructive airways diseaseThe invention y=t furrher induces a.iV novel .

intermediates cescrirec herein.

The svnth.es' s cs tne compounds Cl the l ο i mu I o (I), and cf certain intermediates for use therein, illustrated bv the following i,xa.uplss cud

Preparations, respectively.

The purity of compounds was routinely monitored by thin layer chromatography using Merck Kieselcel 60 plates. 'K Nuclear magnetic res^nence (nmr) scec’^a we^e ^ecorded using Bruker AC 3 00 end Veblen Unitv 300 spectrometers and were in all cases consistent with the proposed structures. Chemical shifts are civen in parrs per million (6) cown.Lj.elc from tetramethvlsilane using standard ccnver. i_icixai abbreviations for the designation Ol m.cjor pecks, e.g singlet (s) , doublet (d) , doublet cf doublets' (dd), triolet (t), cuarret (q), multiple- (m) , end broad (b) . LRMS means lew resolution mass speorrum. Room temperature is 20-25^aC.

£ 6 0 0 / L 6 /d/dV

AP.00751

PREPARATION 1

-Acetylpiperidine-4-carboxyiic acid

OH

Piperidine-4-carboxylic acid (208 g, 1.63 moles) was dissolved in acetic anhydride and the resulting solution heated at reflux under a nitrogen atmosphere for 48 hours. The flask contents were allowed to cool then concentrated under reduced pressure to give a pale yellow oil which solidified on standing. Recrystaliisation from propan-2-ol then afforded the title compound as an off white solid (160 g, 0.94 moles, 58%), mp 164-166 °C (IPA-ethylacetate), δ_Η (300 MHz;CDCI₃) 1.7 (2H, m), 2.0 (2H, m), 2.2 (3H, s), 2.6 (1H, m), 2.85 (1H, m), 3.2 (1H, m), 3.8 (1H, m), and 4.4 (1H, m).

t

PREPARATION 2

1-Acetvlpiperidine-4-(2-oxo-2-phenylethyl)carboxamide

Carbonyldiimidazole (CDI) (212.0 g, 1.31 moles) was added portionwise to a stirred suspension of 1-acetylpiperidine-4-carboxylic acid (200.0 g, 1.17 moles) in dry dichloromethane under nitrogen at room temperature [care CO2 evolution]. The resulting solution was then stirred at room temperature under nitrogen for 2 hours. aAminoacetophenone hydrochloride (210 g, 1.22 moles) was added followed by triethylamine (170 cm³, 1.22 moles) causing a slight exotherm. The

AP .00751 resulting mixture was stirred at ambient temperature under nitrogen overnight. The flask contents were then washed with aqueous hydrochloric acid (2I, 2M) and deionised water (2x11), dried over anhydrous sodium sulphate and concentrated under reduced pressure to give the title compound as an orange solid (300 g, 1.04 moles, 79%), Rf 0.15 (95:5 CH₂CI₂:MeOH), mp 161-162 °C, δ_Η (300 MHz;CDCI₃) 1.7 (2H, m), 1.9 (2H, m), 2.1 (3H, s), 2.5 (1H, m), 2.7 (1H, t), 3.1 (1H, t), 3.9 (1H, d), 4.6 (1H, d), 4.8 (2H, d), 6.6 (1H, s), 7.5 (2H, m), 7.6 (1H, m), and 7.9 (2H, d).

PREPARATION 3

3-Benzoyl-5-(4-( 1 -acetylpiperidinyl))-1.2.4-oxadiazole

1-Acetyipiperidine-4-(2-oxo-2-phenylethyl)carboxamide (294 g, 1.02 moles) was dissolved in glacial acetic acid (1.5 I) with gentle warming. A solution of sodium nitrite (100 g) in deionised water (120 cm³) was then added dropwise over a period of 2 hours with slight cooling from an ice-water bath. The resulting reaction mixture was stirred at ambient temperature for 144 hours adding further sodium nitrite (100 g) in deionised water (120 cm³) every 48 hours. The flask contents were then purged with nitrogen and concentrated under reduced pressure to give a solid residue which was dissolved in dichioromethane (2.5 I) and washed successively with deionised water (500 cm³), aqueous sodium hydroxide (200 cm³, 10% w/v), and deionised water (500 cm³). The resulting organic fraction was dried over anhydrous sodium sulphate and concentrated under reduced pressure to give the title compound as a pale yellow solid, (231 g, 0.77 moles, 77%), Rf 0.26 (95:5 CH₂CI₂:MeOH), mp 97-100 °C, δ_Η (300 MHz;CDCI₃) 1.9 (2H, m), 2.1 (3H, s), 2.2 (2H, m), 2.9 (1H, t), 3.3 (2H, m), 3.9 (1H, d), 4.5 (1H, d), 7.5 (2H, t), 7.6 (1H, t), and 8.2 (2H, d); m/z (LRMS) 322 (MNa⁺), 317 (MNH?), and 300 (MH⁺).

£ 6 0 0 / L 6 /d/dV

AP.00751

PREPARATION 4

3-Benzoyl-5-(4-piperidinyl)-1,2,4-oxadiazole hydrochloride

O

3-Benzoyl-5-{4-(1-acetylpiperidinyl)}-1,2,4-oxadiazole (230 g, 0.77 moles) was dissolved in HCI saturated methanol (2.5 I) and heated at reflux for 24 hours. The flask contents were then allowed to cool and concentrated hydrochloric acid (10 cm³) was added. The reaction mixture was then heated at reflux for a further 20 hours after which tic showed no starting material remaining. The flask contents were then cooled in an ice-acetone bath producing a white solid which was filtered and washed with ethyl acetate to afford the title compound (175 g, 0.58 moles, 75%), mp 224-227 °C, δ_Η (300 MHz;CDCI₃) 2.1 (2H, m), 2.3 (2H, m), 3.1 (2H, m), 3.3 (2H, m),

3.6 (1H, m), 7.6 (2H, m), 7.8 (1H, m), and 9.1 (1H, s); m/z (LRMS) 258 (MH⁺).

PREPARATION 5

3-Benzoyl-5-{4-(1 -benzyipiperidinyl))-1,2,4-oxadiazole

NH.HCI

c

C c

c r

c

C

D <

Benzyl bromide (67 cm³, 0.56 moles) was added to a mixture of 3-benzoyl-5-(4piperidinyl)-1,2,4-oxadiazole hydrochloride (165 g, 0.56 moles) and solid potassium carbonate (194 g, 1.40 moles) in butan-2-one (1.6 I). The flask contents were then stirred at ambient temperature under nitrogen for 48 hours. Deionised water (1.3 I) was then added and the mixture stirred vigorously for 1 hour. The organic layer was collected and the remaining aqueous fraction extracted with ethyl acetate (500 cm³).

AP.00751

The combined organic fractions were then dried over anhydrous sodium sulphate and concentrated to give a pale yellow oil. Flash chromatography (1 kg “Kieselgel 60” silica) eluting with 8% methanol in dichloromethane gave a colourless oil which was azeotroped with toluene to afford the title compound as a white solid (177 g, 0.51 moles, 91%), Rf 0.6 (95:5 CH₂CI₂:MeOH), mp 67-69 °C, δ_Η (300 MHz;CDCI₃)

2.1 (6H, m), 2.9 (2H, d), 3.1 (1H, m), 3.6 (2H, s), 7.3 (5H, m), 7.5 (2H, t), 7.7 (1H, t), and 8.3 (2H, d); m/z (LRMS) 348 (MH⁺).

PREPARATION 6

2-tert-Butyldimethylsiloxvphenylacetonitrile

OH OTBDMS

Mandelonitrile (50 g, 0.38 moles) and imidazole (64 g, 0.94 moles) were dissolved in DMF (100 cm³) and the resulting solution cooled in an ice-water bath. fert-Butyldimethylsilyl chloride (68 g, 0.45 moles) was then added portionwise over a period of 20 minutes. The flask contents were then warmed to 35°C and stirred at that temperature for 18 hours. The reaction mixture was then cooled and partitioned between ethyl acetate (3x100 cm³) and deionised water (100 cm³). The combined organic fractions were then washed with brine (100 cm³), dried over anhydrous magnesium sulphate and concentrated under reduced pressure to give the crude product as a yellow oil. Flash chromatography (600 g kieselgel 60 silica) eluting with 20% dichloromethane in pentane gave the title compound as an oil (77 g, 0.31 moles, 82%), δκ (300 MHz;CDCI₃) 0.1 (3H, s), 0.2 (3H, s), 1.0 (9H, s), 5.5 (1H, s), and 7.4 (5H, m).

AP/P/ 9 7 / 0 0 9 3 0

AP. Ο Ο 7 5 1

PREPARATION 7 a-ferf-Butyldimethylsiloxybenzylamidoxime

OTBDMS

OTBDMS. -^yNH₂NOH

Solid potassium carbonate (54 g, 0.39 moles) was added to a mixture of of 2terf-butyldimethylsiloxyphenylacetonitrile (45 g, 018 moles) and hydroxylamine hydrochloride (25 g, 0.36 moles) in ethanol (450 cm³) and the resulting mixture heated at reflux under nitrogen for 2 hours. The flask contents were then cooled and concentrated under reduced pressure. The resulting residue was partitioned between dichloromethane (3x150 cm³) and deionised water (100 cm³). The combined organic fractions were then washed with brine (100 cm³), dried over anhydrous magnesium sulphate and concentrated under reduced pressure to give the title compound as a yellow solid(53.2 g, 0.18 moles, 100%). δ_Η (300 MHz;CDCI₃) 0.1 (3H, s), 0.2 (3H, s), 1,0 (9H, s), 4.8 (2H, bs), 5.3 (1H, bs), 7.3 (3H, m), and 7.5 (2H, m).

PREPARATION 8

3-(a-te/?-Butvldimethvlsiloxvbenzvl)-5-{4-(1-benzylpiperidinvl))-1,2.4-oxadiazole

OTBDMS .NH

NOH

TBDMSO uiuuu / ιό /α/αν α-ferf-Butyldimethylsiloxybenzylamidoxime (53.2 g, 0.18 moles) was dissolved in THF (400 cm³) and powdered 4A sieves (10 g) were added. The resulting mixture was heated at reflux under nitrogen for 15 minutes then cooled in an icebath. Sodium hydride (8.0 g, 60% dispersion, 0.2 moles) was added portionwise and the flask contents were allowed to warm to room temperature slowiy so as to control effervescence. When hydrogen evolution had ceased, a solution of ethyl N-benzylpiperidine-4-carboxylate (45 g, 0.18 moles) in THF (125 cm³) was added

AP.00751 dropwise. The flask contents were stirred at ambient temperature for 30 minutes then heated at reflux under nitrogen for 1.5 hours. After cooling the reaction mixture was partitioned between ethyl acetate (2x200 cm³) and deionised water (200 cm³). The combined organic fractions were then washed with brine (100 cm³), dried over anhydrous magnesium sulphate and concentrated under reduced pressure to give the title compound as a tan coloured oil (62 g, 0.13 moles, 72%), 5h (300 MHz;CDCI₃) 0.1 (3H, s), 0.2 (3H, s), 1.0 (9H, s), 2.0 (6H, m), 2.9 (3H, m), 3.5 (2H, s), 6.0 (1H, s), 7.3 (8H, m), and 7.5 (2H, m).

PREPARATION 9

3-(a-hvdroxvbenzvi)-5-{4-(1-benzvlpiperidinyl))-t ,2.4-oxadiazole

Tetrabutyl ammonium fluoride (237 cm³, 1 /Win THF) was added dropwise to a stirred solution of 3-(a-ferf-butyldimethylsiloxybenzyl)-5-{4-(1-benzyipiperidinyl)}1,2,4-oxadiazole (62 g, 0.13 moles) in THF (200 cm³) at 0°C. The resulting mixture was then allowed to warm to room temperature and stirred for a further 30 minutes. The flask contents were then partitioned between ethyl acetate (3x200 cm³) and deionised water (200 cm³) and the combined organic fractions washed with brine (100 cm³), dried over anhydrous magnesium sulphate and concentrated under reduced pressure to give the title compound as a yellow solid (45.0 g) (Found C, 70.5; H, 6.5; N, 11.8. C21H23N3O2.72H2O requires C, 70.4; H, 6.8; N, 11.7 %); δ_Η (300 MHz;CDCI₃) 2.0 (6H, m), 2.9 (4H, m), 3.5 (2H, s), 5.9 (1H, d), and 7.3 (10H, m); m/z (LRMS) 350 (MH⁺).

AP/P/ 9 7 / 0 0 9 3 0

AP.00751

PREPARATION 10

3-Benzovl-5-{4-(1-benzvlpiperidinyl))-1,2,4-oxadiazole

KO

Manganese dioxide (206 g, 2.37 moles) was added portionwise to a mechanically stirred solution of 3-(a-hydroxybenzyl)-5-{4-(1-benzylpiperidinyl)}-1,2,4oxadiazole (45.0 g, 0.19 moles) in dry THF (300 cm³) at room temperature over a period of 2 hours. The resulting mixture was then stirred at room temperature for 45 minutes, filtered through an “Arbocel” pad, and concentrated under reduced pressure to give a tacky solid. This residue was redissolved in a minimum quantity of hot diisopropyl ether and the resulting solution was filtered then cooled in an ice-water bath to give the title compound as a beige crystalline solid (26 g, 75 mmoles, 58%). This material was identical in ail respects to that prepared according to Preparation 5.

PREPARATION 11

3-(1,i-Diohenvl-1-hvdroxvmethyl)-5-(4-piperidinvl) -1.2.4-oxadiazole

AP/P/ Q 7 /00930 α-Chloroethylchloroformate (0.27 cm³, 2.5 mmoles) was added dropwise to a stirred solution of 3-(1,1 -diphenyl-1 -hydroxymethyl)-5-{4-(1-benzylpiperidinyl)}1,2,4-oxadiazole (1.00 g, 2.30 mmoles) in dry dichloromethane (10 cm³) at 0°C under nitrogen. The resulting solution was stirred at 0°C for 40 minutes then concentrated under reduced pressure. The resulting residue was dissolved in

ΑΡ. ο Ο 7 5 1 methanol (20 cm³) and heated at reflux for 40 minutes. The flask contents were then cooled, concentrated under reduced pressure and partitioned between dichloromethane (100 cm³) and saturated aqueous sodium bicarbonate (50 cm³). The organic fraction was dried over anhydrous sodium sulphate then concentrated under reduced pressure. Flash chromatography (25 g kieselgel 60 silica) eluting with 5 to 15% methanol in dichloromethane gave the title compound as a white foam (0.68 g, 2.0 mmoles, 80%), Rf 0.05 (90:10 CH₂CI₂:MeOH), δ_Η (300 MHz;CDCI₃) 1.9 (2H, m), 2.2 (2H, m), 2.8 (2H, t), 3.1 (1H, m), 3.3 (2H, m), 4.2 (1H, b), and 7.4 (10H, m); m/z (LRMS) 336 (MH⁺).

PREPARATION 12

3-(1-Cyclobutyl-1-phenyl-1-hydroxvmethvl)-5-(4-piperidinyl) -1.2,4-oxadiazole

α-Chloroethylchloroformate (3.30 g, 23.0 mmoles) was added dropwise to a stirred solution of 3-(1-cyciobutyl-1-phenyl-1-hydroxymethyl)-5-{4-(1benzylpiperidinyl)}-1,2,4-oxadiazole (8.52 g, 21.0 mmoles) in dry toluene (100 cm³). The resulting mixture was then heated at reflux under nitrogen for 90 minutes. The flask contents were then allowed to cool and the reaction mixture concentrated under reduced pressure. The resulting residue was dissolved in methanol (50 cm³) and heated at reflux for 40 minutes. The flask contents were then cooled, concentrated under reduced pressure and partitioned between dichloromethane (100 cm³) and saturated aqueous sodium bicarbonate (50 cm³). The organic fraction was dried over anhydrous sodium sulphate then concentrated under reduced pressure. Flash chromatography (25 g “Kieselgel 60” silica) eluting with 5 to 15% methanol in dichloromethane gave the title compound as a white foam (1.63 g, 5.2 mmoles, 23%), δ_Η (300 MHz;CDCI₃) 1.7

AP/P/ 9 7 / 0 0 9 3 0

AP. Ο Ο 7 5 1 (6Η, m), 2.0 (4Η, m), 2.7 (4H, m), 3.1 (1H, m), 3.2 (2H, m), 3.3 (1H, m), 7.3 (3H, m), and 7.5 (2H, d); m/z (LRMS) 315 (MH⁺).

EXAMPLE 1

3-(1.1-Diphenyl-1-hvdroxymethvl)-5-f4-(1-benzvlpiperidinvl))-1,2,4-oxadiazole

Phenyl lithium (5.0 cm³; 1.8/Win cyclohexane, 9.0 mmoles) was added dropwise to a stirred solution of 3-benzoyl-5-{4-(1-benzylpiperidinyl)}-1,2,4-oxadiazole (3.0 c g, 8.6 mmoles) in dry tetrahydrofuran (40 cm³) at -78°C under a nitrogen atmosphere. The resulting solution was allowed to warm to room temperature over a period of two hours and was then partitioned between ethyl acetate (3x50 ^c cm³) and brine (20 cm³). The combined organic fractions were then dried over C anhydrous sodium sulphate and concentrated under reduced pressure. Flash £ c

chromatography (30 g “Kieselgel 60” silica) eluting with 35% ethyl acetate in hexane gave the title compound (2.9 g, 6.8 mmoles, 76%) Rf 0.8 (ethyl acetate), (Found C, 75.45; H, 6.4; N, 9.8. C27H27N3O2.74H2O requires C, 75.4; H, 6.45; N,

9.8 %); δ_Η (300 MHz;CDCI₃) 2.0 (6H, m), 2.9 (2H, m), 3.5 (2H, s), 3.7 (1H, s), and

7.3 (15H, m); m/z (LRMS) 426 (MH⁺).

EXAMPLE 2

3-(1- r?Butvl-1-phenvl-1-hydroxvmethvl)-5-(4-(1-benzvlpiperidinyl))-1.2,4-oxadiazole

N —O

AP. ο Ο 7 5 1

The title compound was prepared by a similar method to that described in Example 1 substituting butyl lithium (2.5 /Win hexane, 1.1 mole equivalents) in place of phenyl lithium to give the title compound, (Found C, 73.5; H, 7.8; N, 10.0. C₂5H₃₁N₃O2 requires C, 74.0; H, 7.7; N, 10.4 %); δ_Η (300 MHz;CDCI₃) 0.8 (3H, m), 1.3 (4H, m),

2.1 (8H, m), 2.9 (3H, m), 3.2 (1H, s), 3.5 (2H, m), 7.3 (8H, m), and 7.5 (2H, d); m/z (LRMS) 406 (MH⁺).

EXAMPLE 3

3-( 1 -(2-Thienyl)-1 -phenyl-1 -hydroxymethvl)-5-(4-( 1 -benzylpiperidinyl))-1,2.4oxadiazole

n-Butyl lithium (1.3 cm³; 2.5/Win hexane, 3.25 mmoles) was added dropwise to a stirred solution of thiophene (0.3 cm³, 3.0 mmoles) in dry tetrahydrofuran (30 cm³) under nitrogen at -78°C and the resulting solution stirred at -78°C for ten minutes to produce 2-thienyllithium. A solution of 3-benzoyl-5-{4-(1benzylpiperidinyl)}-1,2,4-oxadiazole (1.0 g, 2.9 mmoles) in dry tetrahydrofuran (10 cm³) was then added in one portion and the resulting mixture stirred at -78°C for one hour. The cooling bath was then removed and the flask contents allowed to warm to room temperature over a period of one hour. The reaction mixture was then partitioned between ethyl acetate (3x50 cm³) and brine (20 cm³). The combined organic fractions were then dried over anhydrous sodium sulphate and concentrated under reduced pressure. Flash chromatography (30 g “Kieselgel 60” silica) eluting with 40% ethyl acetate in hexane then gave the title compound (0.83 g, 1.9 mmoles, 66%) (Found C, 68.6; H, 5.9; N, 9.5. C25H25N3O2S.¹/4H₂O requires. C, 68.9; H, 5.9; N, 9.6 %); δ_Η (300 MHz;CDCI₃) 2.1 (6H„m), 2.9 (3H, m),

3.5 (2H, s), 3.95 (1H, s), 6.9 (2H, m), 7.3 (9H, m), and 7.5 (2H, m); m/z (LRMS) 432 (MH⁺).

0E600/Z6 /d/dV

AP.00751

The compounds of the following tabulated examples of the general formula shown below were prepared by reaction of 3-benzoyl-5-{4-(1-benzylpiperjdiny!)}1,2,4-oxadiazole with the appropriate organolithium agent using a similar method to that described in Example 3.

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AP/P/ 97/00930

AP.00751

EXAMPLE 10

3-(1-Cvclobutvl-1-phenyl-1-hvdroxvmethvl)-5-{4-(1-benzvlpiperidinvl))-l,2.4oxadiazole

Cyclobutylbromide (21.7 cm³, 0.23 moles) was added dropwise to a suspension of magnesium turnings (5.7 g, 0.23 moles) in dry diethyl ether (50 cm³) at such a rate so as to maintain reflux. The resulting mixture was then stirred at room temperature for 30 minutes before being added dropwise to a stirred solution of

3-benzoyl-5-(4-(1-benzylpiperidinyl)}-1,2,4-oxadiazole (40.0 g, 0.115 moles) in diethyl ether (400.cm³) and tetrahydrofuran (100 cm³) at -10°C under a nitrogen atmosphere. The resulting mixture was then allowed to warm to room temperature over a period of 2 hours. The flask contents were then cooled and saturated aqueous ammonium chloride (30 cm ) added cautiously. Deionised water (500 cm³) was then added and the mixture extracted with ethyl acetate (2x200 cm³). The combined organic fractions were then dried over anhydrous sodium sulphate and concentrated under reduced pressure. Flash chromatography (500 g “Kieselgel 60” silica) eluting with 40-70% ethyl acetate in pentane then gave the title compound (31.5 g, 0.78 moles, 68%) (Found C, 73.0; H, 7.4; N, 10.1. C₂₅H₂aN₃O₂.7₄H₂O requires C, 73.5; H, 7.3; N, 10.3 %); δ_Η (300 MHz;CDCI₃) 1.9 (12H, m), 2.9 (3H, m), 3.2 (1H, s), 3.3 (1H, m), 3.5 (2H, s), 7.3 (8H, m), and 7.5 (2H, d); m/z (LRMS) 403 (MPT)·

HPLC (“Chiralpak AD” column, 2.5 x 25 cm) eluting with 20% isopropanol, 0.06% trifluoroacetic acid, 0.03 % diethylamine in hexane at 7 cm³/minute then gave (-)-3-(1 -cyclobutyl-1 -phenyl-1 -hydroxymethyl)-5-{4-(1 -benzy Ipipe ridinyl)}-1,2,4oxadiazole , [cc]₀-48°, c 0.1, dichloromethane; and (+)-3-(1-cyclobutyl-1-phenyl1-hydroxymethyl)-5-{4-(1-benzylpiperidinyl)}-1,2,4-oxadiazole , [a]o+51°, c 0.1, mm/ L e /d/dV

AP.00751 dichioromethane; (Found C, 74.3; H, 7.2; N, 10.4. C25H29N3G2 requires C, 74.4; H, 7.2; N, 10.4 %).

EXAMPLES 11-15

The compounds of the following tabulated examples of the general formula shown below were prepared by reaction of 3-benzoyl-5-{4-(1-benzylpiperidinyl)}1,2,4-oxadiazole with the appropriate Grignard reagent using a similar method to that described in Example 10.

AP/P/ 9 7 / 0 0 9 3 0

AP. Ο Ο 7 5 1

AP/P/ 9 7 / 0 0 9 3 0

AP. Ο Ο 7 5 1

EXAMPLE 16

3-(1.1-Diphenyl-1-hvdroxvmethvl)-5-f4-{1-(4-fluorophenvlmethvl)piperidinvl)1-1,2.4oxadiazole

Solid sodium bicarbonate (0.20 g) was added to a stirred solution of 3-(1,1diphenyl-1-hydroxymethyI)-5-(4-piperidinyl)-1,2,4-oxadiazole (0.20 g, 0.6 mmoles) and 4fluoro-phenylmethyl chloride (0.075 cm ³, 0.6 mmoles) in dry dimethylformamide (1 cm³). The resulting mixture was stirred under nitrogen at room temperature for 24 hours then partitioned between ethyl acetate (3x20 cm³) and saturated aqueous sodium carbonate (20 cm³). The combined organic fractions were then dried over anhydrous sodium sulphate 'and concentrated under reduced pressure. Flash chromatography (40 g “Kieselgel 60” silica) eluting with 30-50% ethyl acetate in hexane then gave the title compound (0.07 g, 0.16 mmoles, 26%) (Found C, 72.6; H, 5.95; N, 9.4. C27H26N3O2F requires C, 73.1; H, 5.9; N, 9.5 %); δ_κ (300 MHz;CDCI₃) 2.1 (6H, m), 2.9 (3H, m), 3.5 (2H, s),

3.75 (1H, s), 6.95 (2H, d), and 7.4 (12H, m); m/z (LRMS) 444 (MPT).

EXAMPLES 17 AND 18

The compounds of the following tabulated examples of the general formula shown below were prepared by reaction of 3-(1,1-diphenyl-1-hydroxymethyl)-5(4-piperidinyl)-1,2,4-oxadiazole with the appropriate alkyl halide using a similar method to that described in Example 16.

AP/P/ 9 7 / 00 9 3 0

AP. Ο Ο 7 5 1

Ο £ 6 Ο Ο / Ζ 6 IdldV

AP. Ο Ο 7 5 1

EXAMPLE 19

3-f1-Cyclobutvl-1-Dhenvl-1-hvdroxymethvl)-5-f4-i1-(4-methoxvbenzvllpiperidinvm1.2.4-oxadiazole

NH

OMe

Acetic acid (0.04 g, 0.6 mmoles) was added to a stirred solution of 3-(1cyclobutyl-1 -phenyl-1 -hydroxymethyl)-5-(4-piperidinyl)-1,2,4-oxadiazole (0.16 g, 0.5 mmoles) in dry tetrahydrofuran (15 cm³) at ambient temperature under nitrogen. 4-Methoxybenza!dehyde (0.082 g, 0.6 mmoles) and sodium triacetoxyborohydride (0.212 g, 1.0 mmoles) were then added and the resulting mixture stirred at ambient temperature under nitrogen for 6 hours. The flask contents were then partitioned between dichioromethane (100 cm³) and saturated aqueous sodium bicarbonate. The organic fraction was collected, dried over anhydrous sodium sulphate, and concentrated under reduced pressure to give a brown oil. Flash chromatography (“Kieselgel 60” silica) eluting with 30-50% ethyl acetate in hexane then gave the title compound (0.125 g, 0.28 mmoles, 56%) (Found C, 71.1; H, 7.25; N, 8.6. C2sH3-|N3O3.¹/3 H2O requires C, 71.7; H, 7.2; N, 9.6 %); δ_Η (300 MHz;CDCI₃) 1.6-2.2 (12H, m), 3.2 (1H, s), 3.3 (1H, t), 3.4 (2H, s), 3.8 (3H, s), 6.95 (3H, m), 7.3 (4H, m), and 7.5 (2H, m); m/z (LRMS) 434 (MH⁺).

AP/P/ 97/00930

AP. Ο Ο 7 5 1

EXAMPLES 20 ΤΟ 25

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AP/P/ 9 7 / 0 0 9 3 0

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EXAMPLE 26

3-(1-Cyclobutvl-1-phenvl-1-hvdroxymethvl^,)-5-f4-(1 -(2-phenoxvethyl^,)Diperidinvl)11.2.4-oxadiazole

2- Phenoxybromoethane (0.10 g, 0.5 mmoles) was added to a solution of 3-(1cycIobutyl-1 -phenyl-1 -hydroxymethyl)-5-(4-piperidinyl)-1,2,4-oxadiazole (0.16 g, 0.5 mmoles) in dry tetrahydrofuran (15 cm³) at ambient temperature under nitrogen. Ethyldiisopropylamine (0.13 g, 1.0 mmoles) was then added and the resulting solution stirred at ambient temperature for 7 days. The flask contents were then partitioned between ethyl acetate (3x30cm³) and saturated aqueous sodium bicarbonate solution (10 cm³). The combined organic extracts were then dried and concentrated under reduced pressure. Flash chromatography (“Kieselgel 60” silica) eluting with 3% methanol in dichioromethane then gave the title compound (0.022 g, 0.05 mmoles, 10%) 5_H (300 MHz;CDCI₃) 1.6-2.2 (10H, m), 2.3 (2H, t), 2.8 (2H, t), 2.9 (1H, m), 3.0 (2H, m), 3.2 (1H, s), 3.3 (1H, q), 4.1 (2H, t), 6.9 (3H, m), 7.3 (5H, m), and 7.5 (2H, m); m/z (LRMS) 434 (MIT).

EXAMPLE 27

3- (1-Cvclobutvl-1-phenvl-Thvdroxvmethvl)-5-i4-{1-( a-methvlbenzvhpiperidinyl)11.2.4-oxadiazole

£ 6 0 0 I L 6 ZUZdV

AP. Ο Ο 7 5 1

The above compound was prepared by reaction of 3-(1 -cyclobutyl-1 -phenyl-1hydroxymethyl)-5-(4-piperidinyl)-1,2,4-oxadiazole with α-methylbenzyl bromide using a method similar to that described for Example 26.

(Found C, 73.8; H, 7.4; N, 9.6. C26H31N3O2.V3 H₂O requires C, 73.8; H, 7.5; N,

9.9 %); δ_Η (300 MHz;CDCI₃) 1.3 (3H, s), 1.6-2.2 (12H, m), 2.8 (2H, m), 3.0 (1H, m),

3.2 (1H, s), 3.3 (1H, t), 3.5 (1H, m), 7.2 (8H, m), and 7.5 (2H, m); m/z (LRMS) 419 (MH⁺).

AP/P/ 97/00930

Claims

1. A compound of the formula

N

X

- (I)

R2 wherein R¹ is C-|-C₆ alkyl, halo-(CrC₆ alkyl), C3-C7 cycloalkyl, C₂-C₆ alkynyl, hydroxy-(C₂-C₆ alkynyl), (C1-C4 alkoxy)-(C₂-C₆ alkynyl), aryl, aryl-(Ci-C₄ alkyl), heteroaryl or heteroaryl-(C-i-C₄ alkyl);

R² is H or C1-C4 alkyl;

R³ is aryl, heteroaryl, 2,3-dihydrobenzofuranyl or C4-C7 cycloalkyl;

X is O or S;

and Y is a direct link, -CH₂-, -(CH₂)₂- or -CH₂O-; or a pharmaceutically acceptable salt thereof.

2. A compound as claimed in claim 1 wherein the aryl group is phenyl or naphthyl both optionally substituted by up to 3 substituents each independently selected from C1-C4 alkyl, C1-C4 alkoxy, hydroxy, halo and trifluoromethyi.

3. A compound as claimed in claim 2 wherein the aryl group is selected from phenyl optionally substituted by 1 or 2 substituents each independently selected from C1-C4 alkyl, C1-C4 alkoxy, hydroxy, halo and trifluoromethyi; and naphthyl.

4. A compound as claimed in claim 3 wherein the aryl group is phenyl, fluorophenyi, dichlorophenyl, hydroxyphenyl, methoxyphenyl or naphthyl.

5. A compound as claimed in any one of the preceding claims wherein the heteroaryl group is thienyl, pyridyl, thiazolyl, benzothiazolyl, thiadiazolyl, pyrazolyl or pyrimidinyl, ail optionally substituted by 1 or 2 substituents each independently selected from C1-C4 alkyl, C1-C4 alkoxy, hydroxy and halo.

6. A compound as claimed in claim 5 wherein the heteroaryl group is thienyl, pyridyl, thiazolyl or benzothiazolyl.

7. A compound as claimed in any one of the preceding ciaims wherein R¹ is CrC₆ alkyl; pentafiuoroethyl; C4-C₆ cycloalkyl; ethynyl; -CsC-CH₂OH;

APIPl 97/00930

AP.00751

-C=C-(CH₂)₄-OH;

a phenyl group optionally substituted by 1 or 2 substituents each independently selected from halo, CrC₄ alkyl, Ci-C₄ alkoxy and hydroxy; naphthyl; or a heterocyclic group selected from thienyl, pyridyl, thiazolyl and benzothiazolyl, all optionally substituted by halo, C_rC₄ alkyl, C_rC₄ alkoxy or hydroxy.

8. A compound as claimed in any one of the preceding claims wherein R² is H or CH₃.

9. A compound as claimed in any one of the preceding claims wherein R³ is phenyl optionally substituted by 1 or 2 substituents each independently selected from halo, C-i-C₄ alkyl, CrC₄ alkoxy and hydroxy; 2,3-dihydrobenzofuranyl; C₄-C? cycioalkyl or thienyl.

10. A compound as claimed in any one of the preceding claims wherein X is O.

11. A compound as claimed in any one of the preceding claims wherein Y is a direct link, -CH₂- or -CH₂O-.

12. 3-(1 -Cyclobutyl-1 -phenyl-1 -hydroxymethyl)-5-[4-(1 -benzylpiperidinyl)]-! ,2,4oxadiazole; or (+)-3-(1 -cyclobutyl-1 -phenyi-1 -hydroxymethyl)-5-[4-(1 benzylpiperidinyl)]-1,2,4-oxadiazole.

13. A pharmaceutical composition comprising a compound of the formula (i) or pharmaceutically acceptable salt thereof as claimed in any one of the preceding claims and a pharmaceutically acceptable diluent or carrier.

14. A compound of the formula (I) or pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 12, for use as a medicament.

15. The use of a compound of the formula (i) or pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 12 for the manufacture of a medicament for treating Alzheimer’s disease, age-related memory disorder, irritable bowel syndrome, diverticular disease, urinary incontinence, oesophageal achalasia or chronic obstructive airways disease.

16. A compound of the formula (II):- συ

R³

AP/P/ 97/00930

AP. Ο Ο 7 5 1 ³⁸ where X, Υ, R² and R³ are as defined in claim 1.

17. A process for preparing a compound of the formula (I) as claimed in claim 1 or a pharmaceutically acceptable salt thereof, which comprises reacting a compound of the formula (II) as claimed in claim 16 without a Grignard, organolithium or organocerium reagent of the formula:R¹MgHal, R¹Li or R¹CeCI₂ where Hal is Cl or Br and R¹ is as defined in claim 1, in an organic solvent; said process being followed by, optionally, conversion of the product of the formula (l) into a pharmaceutically acceptable salt.

18. A process according to claim 17, wherein a reagent of the formula R¹MgBr or R¹Li is used, R¹ being as defined in claim 17.

19. A process for preparing a compound of the formula (I) as claimed in claim 1, or a pharmaceutically acceptable salt thereof, which comprises the reaction of a compound of the formula (111) or base salt thereof:- .

c

K o

c c

«*.

cr

E

G «2 wherein R¹ and X are as defined in claim 1, with either (a) a compound of the formula (IV):Q-CH(R²)-Y-R³ -(IV) wherein Q is a leaving group and R², R³ and Y are as defined in claim 1; or (b) an aldehyde or ketone of the formula r³_Y_C-R² —(V) o

wherein R², R³ and Y are as defined in claim 1, in the presence of a reducing agent and in an organic solvent; said process being followed by, optionally, conversion of the product of the formula (I) into a pharmaceutically acceptable salt.

AP. ο Ο 7 5 1

20. A process as claimed in claim 19, wherein the leaving group is tosyloxy, mesyloxy, trifluoromethanesulfonyloxy, CI or Br, and wherein the reducing agent is sodium triacetoxyborohydride or sodium cyanoborohydride.

21. A process as claimed in claim 19 or 20 wherein when the free base of compound (III) is used in (a), and the reaction is carried out in the presence of an acid acceptor.

22. A process according to claim 21 wherein the acid acceptor is sodium bicarbonate or ethyldiisopropylamine.

23. A process according to any one of claims 17 to 22, characterised in that a compound as claimed in any one of claims 2 to 12 is prepared.

24. A process for preparing the compound 3-(1 -cyc!obutyl-1 -phenyl-1 hydroxymethyl)-5-[4-(1 -benzylpiperidinyl)]-1,2,4-oxadiazole, characterised by reacting cyclobutylmagnesium bromide with 3-benzoyl-5-[4-(1-benzylpiperidinyl)]1,2,4-oxadiazole, followed by, if desired, separating said compound into its (+) and (-) enantiomers.

25. A process according to claim 24, characterised in that separation is carried out by HPLC.

26. A method’of treating Alzheimer’s disease, age-related memory disorder, irritable bowel syndrome, diverticular disease, urinary incontinence, oesophageal achalasia or chronic obstructive airways disease in a human patient in need of such treatment, which comprises administering to said patient an effective amount of a compound or pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 12, or of a pharmaceutical composition as claimed in claim 13.