Quinuclidine derivatives as squalene synthase inhibitors

Compounds of formula (I) and their pharmaceutically acceptable salts in which R.sup.1 is hydrogen or hydroxy; R.sup.2 is hydrogen; or R.sup.1 and R.sup.2 are joined together so that CR.sup.1 -CR.sup.2 is a double bond; X is selected from --CH.sub.2 CH.sub.2 --, --CH.dbd.CH--, --C.tbd.C--, --CH.sub.2 O--, --CH.sub.2 NH--, --NHCH.sub.2 --, --CH.sub.2 CO--, --COCH.sub.2 --, --CH.sub.2 S-- and --SCH.sub.2 --; Ar.sup.1 is a phenylene moiety; Ar.sup.2 is a heteroaryl moiety; and wherein one or both of Ar.sup.1 and Ar.sup.2 may optionally bear one or more substituents independently selected from halogeno, hydroxy, amino, nitro, cyano, carboxy, carbamoyl, alkyl, alkenyl, alkynyl, alkoxy, alkylamino, di-alkylamino, N-alkylcarbamoyl, di-N,N-alkylcarbamoyl, alkoxycarbonyl, alkylthio, alkylsulphinyl, alkylsulphonyl, halogeno-alkyl, carboxyalkyl and alkanoylamino; provided that when R.sup.1 is hydroxy, X is not selected from --NHCH.sub.2 -- and --SCH.sub.2 --; are inhibitors of squalene synthase and hence useful in treating medical conditions in which a lowering of cholesterol is beneficial, such as hypercholesterolemia and atherosclerosis. Processes for preparing these derivatives, pharmaceutical compositions containing them are also described together with their use in medicine.

This application is the national phase of PCT/GB93/01802, filed Aug. 24, 
1993. 
FIELD OF THE INVENTION 
This invention concerns heterocyclic compounds which are useful in 
inhibiting squalene synthase, processes for their preparation and 
pharmaceutical compositions containing them. The present invention is also 
concerned with methods of using such heterocyclic compounds in treating 
diseases and medical conditions where inhibition of squalene synthase is 
desirable, for example in treating diseases or medical conditions such as 
hypercholesterolemia and atherosclerosis. 
BACKGROUND TO INVENTION 
Several different classes of compounds have been reported to possess the 
capability of being able to lower cholesterol levels in blood plasma. For 
example agents which inhibit the enzyme HMG CoA reductase, which is 
essential for the production of cholesterol, have been reported to reduce 
levels of serum cholesterol. Illustrative of this class of compounds is 
the HMG CoA reductase inhibitor known as lovastatin which is disclosed in 
U.S. Pat. No 4,231,938. Other agents which are reported to lower serum 
cholesterol include those which act by complexing with bile acids in the 
intestinal system and which are hence termed "bile acid sequestrants". It 
is believed that many of such agents act by sequestering bile acids within 
the intestinal tract. This results in a lowering of the levels of bile 
acid circulating in the enteroheptatic system and promoting replacement of 
bile acids by synthesis in the liver from cholesterol, which synthesis 
results in an upregulation of the heptatic LDL receptor and thus in a 
lowering of circulating blood cholesterol levels. 
Squalene synthase (also referred to in the art as squalene synthetase) is a 
microsomal enzyme which catalyses the first committed step of cholesterol 
biosynthesis. Two molecules of farnesyl pyrophosphate (FFP) are condensed 
in the presence of the reduced form of nicotinamide adenine dinucleotide 
phosphate (NADPH) to form squalene. The inhibition of this committed step 
to cholesterol should leave unhindered biosynthetic pathways to 
ubiquinone, dolichol and isopentenyl t-RNA. Elevated cholesterol levels 
are known to be one of the main risk factors for ischaemic cardiovacsular 
disease. Thus, an agent which inhibits squalene synthase should be useful 
in treating diseases and medical conditions in which a reduction in the 
levels of cholesterol is desirable, for example hypercholesterolemia and 
atherosclerosis. 
Thus far, the design of squalene synthase inhibitors has concentrated on 
the preparation of analogues of the substrate farnesyl pyrophosphate 
(FPP), and hence on compounds which contain phosphorus groups. For 
example, the preparation of phosphorous-containing squalene synthase 
inhibitors is reported in published European Patent Application No. 
409,181; and the preparation of isoprenoid (phosphinylmethyl)phosphonates 
as inhibitors of squalene synthase is reported by Biller et al, J. Med. 
Chem., 1988, 31, 1869. 
Recently, certain quinuclidine derivatives have been reported to inhibit 
squalene synthase (PCT Patent Application No. WO 92/15579, published 17 
Sep. 1992). 
DISCLOSURE OF INVENTION 
The present invention is based on the discovery that certain heterocyclic 
compounds are inhibitors of squalene synthase, and are hence useful in 
treating diseases and medical conditions in which inhibition of squalene 
synthase is desirable. 
According to the present invention there is provided a compound of formula 
I (formula set out hereinafter together with the other chemical formulae 
referred to herein), or a pharmaceutically acceptable salt thereof, 
wherein: 
R.sup.1 is hydrogen or hydroxy; 
R.sup.2 is hydrogen; or 
R.sup.1 and R.sup.2 are joined together so that CR.sup.1 -CR.sup.2 is a 
double bond; 
X is selected from --CH.sub.2 CH.sub.2 --, --CH.dbd.CH--, --C.tbd.C--, 
--CH.sub.2 O--, --CH.sub.2 NH--, --NHCH.sub.2 --, --CH.sub.2 CO--, 
--COCH.sub.2 --, --CH.sub.2 S-- and --SCH.sub.2 --; 
Ar.sup.1 is a phenylene moiety; 
Ar.sup.2 is a heteroaryl moiety; 
and wherein one or both of Ar.sup.1 and Ar.sup.2 may optionally bear one or 
more substituents independently selected from halogeno, hydroxy, amino, 
nitro, cyano, carboxy, carbamoyl, (1-6C)alkyl, (2-6C)alkenyl, 
(2-6C)alkynyl, (1-6C)alkoxy, (1-6C)alkylamino, di-(1-6C)alkyl!amino, 
N-(1-6C)alkylcarbamoyl, di-N,N-(1-6C)alkyl!carbamoyl, 
(1-6C)alkoxycarbonyl, (1-6C)alkylthio, (1-6C)alkylsulphinyl, 
(1-6C)alkylsulphonyl, halogeno-(1-6C)alkyl, carboxy(1-6C)alkyl and 
(1-6C)alkanoylamino; 
provided that when R.sup.1 is hydroxy, X is not selected from --NHCH.sub.2 
-- and --SCH.sub.2 --. 
It will be understood that when formula I compounds contain a chiral 
centre, the compounds of the invention may exist in, and be isolated in, 
optically active or racemic form. The invention includes any optically 
active or racemic form of a compound of formula I which possesses the 
beneficial pharmacological effect of inhibiting squalene synthase. The 
synthesis of optically active forms may be carried out by standard 
techniques of organic chemistry well known in the art, for example by, 
resolution of a racemic form, by synthesis from optically active starting 
materials or by asymmetric synthesis. 
It will also be understood that, insofar as certain of the compounds of the 
formula I may exhibit the phenomenon of tautomerism, for example a 
compound of formula I in which Ar.sup.2 bears a hydroxy substituent, the 
present invention includes any tautomeric form of a compound of formula I 
which possesses the beneficial pharmacological effect of inhibiting 
squalene synthase. 
It is also to be understood that generic terms such as "alkyl" include both 
the straight chain and branched chain groups such as butyl and tert-butyl. 
However, when a specific term such as "butyl" is used, it is specific for 
the straight chain or "normal" butyl group, branched chain isomers such as 
"t-butyl" being referred to specifically when intended. 
It will be appreciated that when R.sup.1 and R.sup.2 are joined so that 
CR.sup.1 -CR.sup.2 is a double bond, the heterocyclic ring in formula I 
will comprise the 2,3-dehydroguinuclidine moiety shown in formula Ia. 
As used herein, the term heteroaryl encompasses monocyclic aromatic 
heterocycles which contain (in addition to carbon atoms) one, two, three 
or four heteroatoms selected from nitrogen, oxygen and sulphur; bicyclic 
aromatic heterocycles of about 8 to 10 ring atoms and containing one, two, 
three or four heteroatoms selected from nitrogen, oxygen and sulphur, and 
in particular benz-derivatives of said monocyclic aromatic heterocycles. 
Suitable values for Ar.sup.2 include, for example, a 5-membered or 
6-membered aromatic (that is, fully unsaturated) heterocyclic ring 
containing one, two, three or four heteroatoms (and in particular one, two 
or three heteroatoms) selected from nitrogen, oxygen and sulphur, and a 
5-membered or 6-membered aromatic heterocyclic ring containing one, two, 
three or four heteroatoms (and in particular one, two or three 
heteroatoms) selected from nitrogen, oxygen and sulphur which is fused to 
a benzene ring. 
In particular Ar.sup.2 may comprise a heteroaryl moiety containing up to 
three heteroatoms selected from nitrogen, oxygen and sulphur. Thus, in 
particular, Ar.sup.2 the heteroaryl moiety, may comprise a fully 
unsaturated heterocyclic ring which contains one, two or three heteroatoms 
selected from nitrogen, oxygen and sulphur as ring atoms, and may be 
attached to Ar.sup.1 through any available ring atom. 
Suitable values for Ar.sup.1 the phenylene moiety, include 1,2-phenylene; 
1,3-phenylene and 1,4-phenylene. 
A particular value for an optional substituent which may be present on 
Ar.sup.1 or Ar.sup.2 is, for example, 
for alkyl; (1-4C)alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, 
isobutyl or sec-butyl; 
for alkenyl; (2-4C)alkenyl, such as allyl, prop-2-enyl, but-2-enyl or 
2-methyl-2-propenyl; 
for alkynyl; (2-4C)alkynyl, such as prop-2-ynyl or but-2-ynyl; 
for alkoxy; (1-4C)alkoxy, such as methoxy, ethoxy, propoxy, isopropoxy or 
butoxy; 
for alkylamino; (1-4C)alkylamino, such as methylamino, ethylamino, 
propylamino or butylamino; 
for di-alkylamino; dimethylamino, diethylamino, methylpropylamino or 
dipropylamino; 
for alkylcarbamoyl; N-methylcarbamoyl, N-ethylcarbamoyl or 
N-propylcarbamoyl; 
for di-alkylcarbamoyl; N,N-dimethylcarbamoyl or N,N-diethylcarbamoyl; 
for alkoxycarbonyl; methoxycarbonyl, ethoxycarbonyl or propoxycarbonyl; 
for alkylthio; methylthio, ethylthio, propylthio, isopropylthio or 
butylthio; 
for alkylsulphinyl; methylsulphinyl, ethylsulphinyl, propylsulphinyl, 
isopropylsulphinyl or butylsulphinyl; 
for alkylsulphonyl; methylsulphonyl, ethylsulphonyl, propylsulphonyl, 
isoproylsulphonyl or butylsulphonyl; 
for halogeno; fluoro, chloro, bromo or iodo; 
for halogenoalkyl; halogenoalkyl containing one, two or three halo groups 
selected from fluoro, chloro, bromo and iodo and an alkyl group selected 
from methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl and sec-butyl, 
(in particular fluoromethyl, difluoromethyl or trifluoromethyl); 
for carboxyalkyl; carboxymethyl, 1-carboxyethyl, 2-carboxyethyl and 
3-carboxypropyl; and 
for alkanoylamino; formamido, acetamido, propionamido, iso-propionamido, 
butyramido or iso-butyramido. 
Particular values for Ar.sup.2 include, for example, furyl, pyrrolyl, 
thienyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, imidazolyl, 
oxazolyl, isooxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, triazolyl, 
tetrazolyl, benzfuranyl, quinolyl, isoquinolyl, benzimidazolyl, indolyl, 
pyrazolyl, thiadiazolyl, benzthiazolyl and benzoxazolyl. 
More particular values of Ar.sup.2 include, for example, pyridyl, 
pyrazolyl, thiadiazolyl, benzthiadiazolyl and oxadiazolyl. 
In general, it is preferred for example that Ar.sup.2 is a 5-membered or 
6-membered heteroaryl ring containing (in addition to carbon atoms) one, 
two or three heteroatoms selected from nitrogen, oxygen and sulphur. Thus 
preferred values for Ar.sup.2 will include, for example, pyridyl, 
thiadiazolyl or oxadiazolyl (especially pyridyl or oxadiazolyl). 
A particular value for Ar.sup.1 is, for example, 1,3-phenylene or 
1,4-phenylene. 
In general it is preferred, for example, that Ar.sup.1 is 1,4-phenylene. 
In general, it is preferred that Ar.sup.1 is optionally unsubstituted or 
substituted by one, two or three substituents independently selected from 
those mentioned above; and that Ar.sup.2 is optionally unsubstituted or 
substituted by one, two or three substituents from those mentioned above. 
In a particular embodiment, one or both of Ar.sup.1 and Ar.sup.2 may 
optionally bear one or more substituents selected from halogeno, hydroxy, 
nitro, (1-6C)alkyl, (2-6C)alkenyl, (1-6C)alkoxy, (1-6C)alkylthio, 
(1-6C)alkylsulphinyl, (1-6C)alkoxycarbonyl, (1-6C)alkylsulphonyl, 
(1-6C)alkanoylamino and halogeno-(1-6C)alkyl. 
A particular value for X is, for example, --CH.sub.2 CH.sub.2 --, 
--CH.dbd.CH--, --C.tbd.C--, --CH.sub.2 O--, --CH.sub.2 NH-- or --CH.sub.2 
S--. A more particular values for X is, for example, --CH.sub.2 CH.sub.2 
--, --CH.dbd.CH--, --C.tbd.C-- or --CH.sub.2 O--. In general it is 
preferred, for example, that X is --CH.dbd.CH--, --C.tbd.C-- or --CH.sub.2 
O--. 
In general it is preferred, for example, that R.sup.1 is hydroxy and 
R.sup.2 is hydrogen. 
Specific values of Ar.sup.2 (optionally substituted as hereinbefore 
defined) include, for example, 2-pyridyl, 3-pyridyl, 4-pyridyl, 
1-pyrrolyl, 5-pyrimidinyl, 2-indolyl, 2-quinolyl, 3-pyazolyl, 
1-imidazolyl, 2-methyl-tetrazol-5-yl, 1-pyrazolyl, 2-oxazolyl, 
5-isoxazolyl, 2-thiazolyl, 1,2,4-thiadiazol-5-yl, 2-benz-1,3-oxazolyl, 
2-benz-1,3-thiazolyl, 1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl and 
1,3,4-oxadiazol-2-yl. 
Specific optional substituents for Ar.sup.2 include hydroxy, (1-6C)alkyl 
such as methyl, ethyl or isopropyl, (1-6C)alkoxy such as methoxy and 
(1-6C)alkoxycarbonyl such as ethoxycarbonyl. 
Further specific values for Ar.sup.2 include, for example, 2-thienyl, 
2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 5-pyrimidyl, 3-pyrazinyl, 
2-pyridazinyl, 1-imidazolyl, 2-imidazolyl, 3-pyrazinyl, 2-pyridazinyl, 
1,2,3-triazol-1-yl, 1,2,3-triazol-3-y, 3-quinolyl, 4-quinolyl, 
3-isoquinolyl, 4-isoquinolyl, 1-benzimidazolyl, 2-indolyl and 3-indolyl, 
which may optionally bear one or two substituents independently selected 
from fluoro, chloro, bromo, iodo, hydroxy, nitro, methyl, ethyl, propyl, 
isopropyl, butyl, isobutyl, sec-butyl, allyl, methoxy, ethoxy, propoxy, 
isopropoxy, butoxy, methylthio, ethylthio, propylthio, isopropylthio, 
butylthio, methylsulphinyl, ethylsulphinyl, propylsulphinyl, 
isopropylsulphinyl, butylsulphinyl, methylsulphonyl, ethylsulphonyl, 
propylsulphonyl, isoproylsulphonyl, butylsulphonyl, acetamido, 
propionamido, iso-propionamido, fluoromethyl, difluoromethyl and 
trifluoromethyl. 
Specific values for Ar.sup.1 include, for example, an unsubstituted 
1,4-phenylene moiety and a 1,4-phenylene moiety having one or substituents 
independently selected from fluoro, chloro, bromo, iodo, hydroxy, nitro, 
methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, allyl, 
methoxy, ethoxy, propoxy, isopropoxy, butoxy, methylthio, ethylthio, 
propylthio, isopropylthio, butylthio, methylsulphinyl, ethylsulphinyl, 
propylsulphinyl, isopropylsulphinyl, butylsulphinyl, methylsulphonyl, 
ethylsulphonyl, propylsulphonyl, isoproylsulphonyl, butylsulphonyl, 
acetamido, propionamido, iso-propionamido, fluoromethyl, difluoromethyl 
and trifluoromethyl. 
A preferred optional substituent for Ar.sup.1 is for example, (2-6C)alkenyl 
such as allyl. 
In a specific embodiment Ar.sup.1 and Ar.sup.2 are both unsubstituted. 
In a further embodiment of the present invention, R.sup.1 and R.sup.2 are 
both hydrogen; and Ar.sup.1 and Ar.sup.2 have any of the meanings defined 
above. 
In a further embodiment of the present invention, R.sup.1 is hydroxy; 
R.sup.2 is hydrogen; and Ar.sup.1 and Ar.sup.2 have any of the meanings 
defined above. 
In a further embodiment of the present invention, R.sup.1 and R.sup.2 are 
joined together so that CR.sup.1 -CR.sup.2 is a double bond; and Ar.sup.1 
and Ar.sup.2 have any of the meanings defined above. 
In a further embodiment of the present invention there is provided a 
compound of formula I, or a pharmaceutically acceptable salt thereof, 
wherein: 
R.sup.1 is hydrogen or hydroxy; 
R.sup.2 is hydrogen; or 
R.sup.1 and R.sup.2 are joined together so that CR.sup.1 -CR.sup.2 is a 
double bond; 
X is selected from --CH.sub.2 CH.sub.2 --, --CH.dbd.CH--, --C.tbd.C--, 
--CH.sub.2 O--, --OCH.sub.2 --, --CH.sub.2 NH--, --NHCH.sub.2 --, 
--CH.sub.2 CO--, --COCH.sub.2 --, --CH.sub.2 S-- and --SCH.sub.2 --; 
Ar.sup.1 is a phenylene moiety; 
Ar.sup.2 is a heteroaryl moiety containing up to three heteroatoms selected 
from nitrogen, oxygen and sulphur; 
and wherein one or both of Ar.sup.1 and Ar.sup.2 may optionally bear one or 
more substituents independently selected from halogeno, hydroxy, amino, 
nitro, cyano, carboxy, carbamoyl, (1-6C)alkyl, (2-6C)alkenyl, 
(2-6C)alkynyl, (1-6C)alkoxy, (1-6C)alkylamino, di-(1-6C)alkyl!amino, 
N-(1-6C)alkylcarbamoyl, di-N,N-(1-6C)alkyl!carbamoyl, 
(1-6C)alkoxycarbonyl, (1-6C)alkylthio, (1-6C)alkylsulphinyl, 
(1-6C)alkylsulphonyl, halogeno-(1-6C)alkyl, carboxy(1-6C)alkyl and 
(1-6C)alkanoylamino; 
provided that when R.sup.1 is hydroxy, X is not selected from --NHCH.sub.2 
-- and --SCH.sub.2 --; 
and excluding those compounds in which X is --OCH.sub.2 -- and R.sup.1 and 
R.sup.2 are both hydrogen or R.sup.1 and R.sup.2 are joined together so 
that CR.sup.1 -CR.sup.2 is a double bond, and their pharmaceutically 
acceptable salts. 
Particular, preferred and specific values are the appropriate values 
mentioned above. Thus it is generally preferred that R.sup.1 is hydroxy 
and R.sup.2 is hydrogen. 
In a particular, one or both of Ar.sup.1 and Ar.sup.2 may optionally bear 
one or more substituents selected from halogeno, hydroxy, nitro, 
(1-6C)alkyl, (2-6C)alkenyl, (1-6C)alkoxy, (1-6C)alkylthio, 
(1-6C)alkylsulphinyl, (1-6C)alkylsulphonyl, (1-6C)alkanoylamino and 
halogeno-(1-6C)alkyl. 
In particular, Ar.sup.2 is, for example, furyl, pyrrolyl, thienyl, pyridyl, 
pyrazinyl, primidinyl, pyridazinyl, imidazolyl, oxazolyl, isooxazolyl, 
thiazolyl, isothiazolyl, oxadiazolyl, thiazolyl, 1,2,3-triazolyl, 
1,2,4-triazolyl, benzfuranyl, quinolyl, isoquinolyl, benzimidazolyl and 
indolyl. 
A further group of values for Ar.sup.2 of interest is, for example, 
pyridyl, pyrazinyl, primidinyl, pyridazinyl and imidazolyl (especially 
pyridyl such as 2-pyridyl or 3-pyridyl and imidazolyl such as 
1-imidazolyl). 
Values of interest for Ar.sup.2 include pyridyl; values of interest for X 
include --CH.dbd.CH-- or --C.tbd.C--. 
In a particular embodiment the present invention provides a compound of 
formula I, or a pharmaceutically acceptable salt thereof, wherein: 
R.sup.1 is hydrogen or hydroxy; R.sup.2 is hydrogen; or 
R.sup.1 and R.sup.2 are joined together so that CR.sup.1 -CR.sup.2 is a 
double bond; 
X is selected from --CH.sub.2 CH.sub.2 --, --CH.dbd.CH--, --C.tbd.C--, 
--CH.sub.2 O--, --CH.sub.2 NH--, and --CH.sub.2 S--; 
Ar.sup.1 is a 1,4-phenylene moiety; 
Ar.sup.2 is a heteroaryl moiety containing one, two or three heteroatoms 
selected from nitrogen, oxygen and sulphur; 
and wherein one or both of Ar.sup.1 and Ar.sup.2 may optionally bear one or 
more substituents independently selected from halogeno, hydroxy, amino, 
nitro, cyano, carboxy, carbamoyl, (1-6C)alkyl, (2-6C)alkenyl, 
(2-6C)alkynyl, (1-6C)alkoxy, (1-6C)alkylamino, di-(1-6C)alkyl!amino, 
N-(1-6C)alkylcarbamoyl, di-N,N-(1-6C)alkyl!carbamoyl, 
(1-6C)alkoxycarbonyl, (1-6C)alkylthio, (1-6C)alkylsulphinyl, 
(1-6C)alkylsulphonyl, halogeno (1-6C)alkyl, carboxy(1-6C)alkyl and 
(1-6C)alkanoylamino. 
Particular, preferred and specific values are the appropriate values 
mentioned above. 
In a further embodiment of interest there is provided a compound of formula 
I, or a pharmaceutically acceptable salt thereof, wherein: 
R.sup.1 is hydroxy; R.sup.2 is hydrogen; X is selected from --CH.sub.2 
CH.sub.2 --, --CH.dbd.CH--, --C.tbd.C-- and --CH.sub.2 O--; 
Ar.sup.1 is a 1,4-phenylene moiety; 
Ar.sup.2 is a 5-membered or 6-membered heteroaryl moiety containing one or 
two nitrogen atoms (especially pyridyl or imidazolyl); 
and wherein one or both of Ar.sup.1 and Ar.sup.2 may optionally bear one or 
more substituents independently selected from halogeno, hydroxy, amino, 
nitro, cyano, carboxy, carbamoyl, (1-6C)alkyl, (2-6C)alkenyl, 
(2-6c)alkynyl, (1-6C)alkoxy, (1-6C)alkylamino, di-(1-6C)alkyl!amino, 
N-(1-6C)alkylcarbamoyl, di-N,N-(1-6C)alkyl!carbamoyl, 
(1-6C)alkoxycarbonyl, (1-6C)alkylthio, (1-6C)alkylsulphinyl, 
(1-6C)alkylsulphonyl, halogeno (1-6C)alkyl, carboxy(1-6C)alkyl and 
(1-6C)alkanoylamino. 
Particular, preferred and specific values are the appropriate values 
mentioned above. 
In a particular embodiment the present invention provides a compound of 
formula I, or a pharmaceutically acceptable salt thereof, wherein: 
R.sup.1 is hydroxy; R.sup.2 is hydrogen; 
X is selected from --CH.dbd.CH--, --C.tbd.C-- and --CH.sub.2 O--; 
Ar.sup.1 is a 1,4-phenylene moiety; 
Ar.sup.2 is a heteroaryl moiety containing one, two or three heteroatoms 
selected from nitrogen, oxygen and sulphur; 
and wherein one or both of Ar.sup.1 and Ar.sup.2 may optionally bear one or 
more substituents independently selected from halogeno, hydroxy, amino, 
nitro, cyano, carboxy, carbamoyl, (1-6C)alkyl, (2-6C)alkenyl, 
(2-6C)alkynyl, (1-6C)alkoxy, (1-6C)alkylamino, di-(1-6C)alkyl!amino, 
N-(1-6C)alkylcarbamoyl, di-N,N-(1-6C)alkyl!carbamoyl, 
(1-6C)alkoxycarbonyl, (1-6C)alkylthio, (1-6C)alkylsulphinyl, 
(1-6C)alkylsulphonyl, halogeno(1-6C)alkyl, carboxy(1-6C)alkyl and 
(1-6C)alkanoylamino. 
Particular, preferred and specific values are the appropriate values 
mentioned above. 
In a further embodiment the present invention provides a compound of 
formula I, or a pharmaceutically acceptable salt thereof, wherein: 
R.sup.1 is hydroxy; R.sup.2 is hydrogen; X is selected from --CH.sub.2 
CH.sub.2 --, --CH.dbd.CH--, --C.tbd.C-- and --CH.sub.2 O--; Ar.sup.1 is a 
1,4-phenylene moiety; and 
Ar.sup.2 is a 5- or 6-memebered heteroaryl moiety containing up to three 
heteroatoms independently selected from nitrogen, oxygen and sulphur; 
and wherein one or both of Ar.sup.1 and Ar.sup.2 may optionally bear one or 
more substituents independently selected from halogeno, hydroxy, amino, 
nitro, cyano, carboxy, carbamoyl, (1-6C)alkyl, (2-6C)alkenyl, 
(2-6C)alkynyl, (1-6C)alkoxy, (1-6C)alkylamino, di-(1-6C)alkyl!amino, 
N-(1-6C)alkylcarbamoyl, di-N,N-(1-6C)alkyl!carbamoyl, 
(1-6C)alkoxycarbonyl, (1-6C)alkylthio, (1-6C)alkylsulphinyl, 
(1-6C)alkylsulphonyl, halogeno-(1-6C)alkyl, carboxy(1-6C)alkyl and 
(1-6C)alkanoylamino. 
Particular, preferred and specific values are the appropriate values 
mentioned above. 
Further compounds (and their pharmaceutcially acceptable salts of interest 
include, for example those in which: 
(a) R.sup.1 is hydroxyl R.sup.2 is hydrogen; X is --C.tbd.C--; Ar.sup.1 is 
a 1,4-phenylene moiety; and Ar.sup.2 is a 5- or 6-memebered heteroaryl 
moiety containing up to three heteroatoms independently selected from 
nitrogen, oxygen and sulphur (especially oxadiazolyl or thiadiazolyl); 
(b) R.sup.1 is hydroxy; R.sup.2 is hydrogen; X is selected from --CH.sub.2 
CH.sub.2 --, --CH.dbd.CH--, --C.tbd.C-- and --CH.sub.2 O--; Ar.sup.1 is a 
1,4-phenylene moiety; and Ar.sup.2 is an oxadiazolyl moiety; 
(c) R.sup.1 is hydroxy; R.sup.2 is hydrogen; X is --CH.sub.2 O--; Ar.sup.1 
is a 1,4-phenylene moiety; and Ar.sup.2 is a 5- or 6-memebered heteroaryl 
moiety containing up to three heteroatoms independently selected from 
nitrogen, oxygen and sulphur (especially oxadiazolyl or thiadiazolyl); and 
in each case one or both of Ar.sup.1 and Ar.sup.2 may optionally bear one 
or more substituents independently selected from halogeno, hydroxy, amino, 
nitro; cyano, carboxy, carbamoyl, (1-6C)alkyl, (2-6C)alkenyl, 
(2-6C)alkynyl, (1-6C)alkoxy, (1-6C)alkylamino, di-(1-6C)alkyl!amino, 
N-(1-6C)alkylcarbamoyl, di-N,N-(1-6C)alkyl!carbamoyl, 
(1-6C)alkoxycarbonyl, (1-6C)alkylthio, (1-6C)alkylsulphinyl, 
(1-6C)alkylsulphonyl, halogeno-(1-6C)alkyl, carboxy(1-6C)alkyl and 
(1-6C)alkanoylamino. 
Further compounds (and pharmaceutically acceptable salts thereof) of 
interest include those of formula I wherein: 
R.sup.1 is hydroxy; R.sup.2 is hydrogen; X is selected from --CH.sub.2 
CH.sub.2 --, --CH.dbd.CH--, --C.tbd.C and --CH.sub.2 O-- (especially 
--CH.dbd.CH-- or --C.tbd.C); 
Ar.sup.1 is a 1,4-phenylene moiety; and Ar.sup.2 is a pyridyl moiety. 
Compounds of the invention which are of particular interest include the 
compounds described in the accompanying Examples (and their 
pharmaceutically-acceptable salts), and are hence provided as a further 
feature of the present invention. In particular the present invention 
provides a compound (or a pharmaceutically acceptable salt) selected from 
those described in Examples 4, 8, 11, 31, 32, 33, 34, 41, 43, 44 and 49. 
A suitable pharmaceutically-acceptable salt of the present invention 
comprises an acid-addition salt derived from an inorganic or organic acid 
which provides a pharmaceutically-acceptable anion. Thus, examples of 
salts of the present invention include acid-addition salts with 
hydrochloric, hydrobromic, nitric, sulphuric, phosphoric, trifluoroacetic, 
citric, tartaric, succinic, maleic, fumaric or acetic acid. In addition, 
suitable pharmaceutically-acceptable salts include where the compound of 
formula I is sufficiently acidic, for example where the compound of 
formula I bears an acidic substituent such as carboxy! those formed with a 
base which affords a pharmaceutically acceptable cation. Suitable bases 
include an alkali metal salt (such as a sodium or potassium salt), an 
alkaline earth metal salt (such as a calcium or magnesium salt), an 
ammonium salt or a salt with an organic base which affords a 
physiologically-acceptable cation such as a salt with methylamine, 
dimethylamine, triethylamine, piperidine or morpholine. 
The compounds of the present invention may be obtained by standard 
procedures of organic chemistry already known to be applicable to the 
preparation of structurally analogous compounds. Such procedures for the 
preparation of the compounds of formula I, or pharmaceutically acceptable 
salts thereof, are provided as a further feature of the present invention 
and are illustrated by the following processes in which the various 
generic radicals, for example, R.sup.1, R.sup.2, X, Ar.sup.1 and Ar.sup.2 
may take any of the meanings hereinbefore defined. 
Thus, according to the present invention there is also provided a process 
for preparing a compound of formula I, or a pharmaceutically-acceptable 
salt thereof, which process comprises: 
(a) For those compounds of formula I in which R.sup.1 and R.sup.2 are both 
hydrogen, reducing a compound of formula I in which R.sup.1 and R.sup.2 
are joined together so that CR.sup.1 -CR.sup.2 is a double bond. 
The reduction may be carried out, for example, by catalytic hydrogenation, 
or by reaction with a suitable reducing agent. Suitable reaction 
conditions include, for example, catalytic hydrogenation using a catalyst 
which comprises a noble metal. Particular catalysts include palladium, 
platinum and nickel (especially when in the finely divided state known as 
raney nickel), and catalysts in which the noble metal is supported on an 
inert carrier such as carbon. A specific example of a supported catalyst 
is Pd/C. The reduction is conveniently carried out in a solvent of, for 
example, an alcohol (such as ethanol), and at (or near) ambient 
temperature and optionally under pressure. 
Further suitable reaction conditions include, for example, reduction with a 
borane such as diborane. The reaction is generally carried out in an inert 
solvent of, for example, tetrahydrofuran or methyl t-butyl ether at, for 
example, 0.degree.-60.degree. C. It may be preferable to cool the reaction 
below ambient temperature (e.g. to about 0.degree. C.) during the 
reduction. The borane generated may be hydrolysed by treatment with an 
organic acid such as acetic acid, which hydrolysis may be carried out at 
0.degree.-60.degree. C., and may be accelerated by heating (e.g. 
refluxing). 
(b) For compounds of formula I in which R.sup.1 and R.sup.2 are joined 
together so that CR.sup.1 -CR.sup.2 is a double bond, dehydrating a 
compound of formula I in which R.sup.1 is hydroxy and R.sup.2 is hydrogen. 
The dehydration may be carried out using an acid such as sulphuric acid 
(e.g. concentrated sulphuric acid), or p-toluene sulphonic acid. The 
reaction is conveniently carried out with heating, and conveniently an 
inert solvent is employed. For example, the reaction may be carried out 
using sulphuric acid at temperatures of about 70.degree.-130.degree. C.; 
or using p-toluene sulphonic acid in a hydrocarbon solvent of, for 
example, toluene or xylene at ambient temperature to reflux, and 
preferably at reflux. The dehydration may also be carried out using 
trifluoroacetic acid in an inert solvent such as dichloromethane (at 
ambient temperature to reflux temperature). 
(c) For compounds of formula I in which R.sup.1 and R.sup.2 are joined 
together so that CR.sup.1 -CR.sup.2 is a double bond, treating a compound 
of formula II in which Z is a leaving group with a base. 
Suitable values for Z include, for example, halogen such as chloro, bromo, 
iodo, or a methylsulphonyloxy or toluenesulphonyloxy group. Suitable bases 
include hydroxide (such as potassium or sodium hydroxide), and alkoxide 
(such as potassium t-butoxide or sodium ethoxide). 
The reaction is conveniently carried out in the presence of a solvent, 
preferably a polar organic solvent. Suitable solvents include, for 
example, an alcohol (such as ethanol), or an aprotic solvent such as 
dimethylformamide or N-methylpyrrolidone. The reaction may be carried out 
at ambient temperature or at an elevated temperature, such as at a 
temperature between ambient and the reflux temperature of the reaction 
mixture. This method is generally preferred over that described in (b) 
when X is --OCH.sub.2 -- or --SCH.sub.2 --. 
The compounds of formula II may be prepared from a compound of formula I in 
which R.sup.1 is hydroxy. For example, where Z is halogen the compound of 
formula I in which R.sup.1 is hydroxy and R.sup.2 is hydrogen may be 
reacted with the appropriate phosphorous halide (e.g. PCl.sub.5, PBr.sub.3 
or PI.sub.3), or where Z is chloro, by reaction with thionyl chloride. The 
compound of formula I in which R.sup.1 is hydroxy may be reacted with 
mesyl chloride to the compound in which Z is methylsulphonyloxy; and with 
tosyl chloride to give Z is toluene sulphonyloxy. 
(d) For those compounds of formula I in which X is --CH.sub.2 CO--, 
reacting an organometallic compound of formula Ar.sup.2 --Ar.sup.1 --M in 
which M is a metal atom or a derivative thereof, with a compound of 
formula III. 
Suitable values for M include, for example, magnesium and lithium. In the 
case where M is magnesium it is conveniently present in the form of a 
derivative of formula --MgX where X is a halogen atom such as iodo or 
bromo, so that the organometallic compound of formula III is in the form 
known as a Grignard Reagent. The reaction is generally carried out in an 
inert solvent such as dry diethyl ether or tetrahydrofuran. For example, 
the reaction may be carried out at a temperature between 0.degree. C. and 
the reflux temperature of the reaction mixture. 
The compounds of formula Ar.sup.2 --Ar.sup.1 --M may be prepared from the 
corresponding compound of formula Ar.sup.2 --Ar.sup.1 -"hal" in which 
"hal" is a halogen atom, such as iodo or bromo as is yell known in the 
art. 
e) For those compounds of formula I in which X is --CH.sub.2 --NH-- or 
--NHCH.sub.2 --, reducing a compound of formula I in which X is 
--CH.dbd.N-- or --N.dbd.CH-- (as appropriate). 
The reaction may be carried out using a chemical reducing agent such as a 
hydride in a solvent such as an alcohol at ambient temperature. Thus, in a 
particular example, the reduction may be carried out using sodium 
borohydride in a solvent of methanol at ambient temperature. The reduction 
may also be carried out by selective catalytic hydrogenation using similar 
conditions to those described under (a) above. 
It will be appreciated that the preferred method of reduction will depend 
upon the value of X. Thus, for example, where debenzylation is possible 
(e.g. when X is --NHCH.sub.2 --), it is generally preferred that a 
chemical reducing agent is employed. 
The compounds of formula I in which X is --CH.dbd.N-- may be prepared by 
reaction of a compound of formula IV with a compound of formula Ar.sup.2 
--Ar.sup.1 --NH.sub.2. The reaction is generally carried out in an inert 
hydrocarbon solvent such as toluene or benzene, with heating (e.g. at 
reflux) and the reaction may be accelerated by removing water generated in 
the reaction by azeotropic distillation. Similarly, the compounds of 
formula I in which X is --N.dbd.CH-- may be prepared by reaction of a 
compound of formula Ar.sup.2 --Ar.sup.1 --CHO with a compound of formula 
V. 
f) For those compounds of formula I in which X is --CH.sub.2 NH--, 
--CH.sub.2 O--, --CH.sub.2 S--, R.sup.1 is hydroxy and R.sup.2 is 
hydrogen, reacting a compound of formula Ar.sup.2 --Ar.sup.1 --Z in which 
Z is --NH.sub.2, --OH or SH as appropriate with a compound of formula VI. 
The reaction is conveniently carried out in a solvent such an inert 
hydrocarbon e.g. toluene with heating. The reaction may be facilitated by 
the presence of acid or base. 
The compound of formula VI is conveniently generated in situ, by, for 
example, treating quinuclidin-3-one with trimethylsulphoxonium iodide in 
the presence of a base of, for example, an alkali metal hydride such as 
sodium hydride and in a solvent such as dimethylformamide, or an alkali 
metal hydroxide such as sodium hydroxide in a solvent such as an aqueous 
solvent. 
The compound of formula VI may also be prepared from a "halohydrin" as is 
well known in the art. The halohydrin may be prepared, for example, by 
addition of HOCl to the corresponding olefin and the halobydrin treated 
with base (e.g. NaOH) to give the compound of formula VI. 
g) For compounds of formula I in which X is --CH=CH--, reacting a compound 
of formula VII with a compound of formula IV in the presence of a base. 
Suitable bases include alkoxides, such as potassium t-butoxide, and the 
reaction is conveniently carried out in an inert solvent such as 
tetrahydrofuran with cooling below ambient temperature e.g. -40.degree. C. 
to 0.degree. C.); and metal hydrides such as sodium hydride in a solvent 
such as dimethyl formamide or dimethylsuphoxide. A particularly suitable 
base is, for example, sodium dimsyl which may conveniently be used in a 
solvent such as dimethyl suphoxide. 
The compounds of formula XI may be prepared by reaction of a compound of 
formula Ar.sup.2 --Ar.sup.1 --CH.sub.2 -hal in which "hal" is halogen, 
such as chloro, with triphenylphosphine as is well known in the art. 
h) For those compounds of formula I in which X is --CH.sub.2 CH.sub.2 --, 
reducing a compound of formula I in which X is --CH.dbd.CH--. 
The reaction may conveniently be carried out by catalytic hydrogenation 
using conditions similar to those mentioned in (a) above. 
In an alternative synthesis a compound of formula Ar.sup.2 --Ar.sup.1 
--CH.sub.2 CH.sub.2 -hal wherein "hal" represents a halogen atom such as 
bromo, is reacted with quinuclidin-3-one in the presence of sec-butyl 
lithium, with cooling (e.g. -70.degree. C.) in an inert solvent such as 
tetrahydrofuran. 
i) For compounds of formula I in which X is --COCH.sub.2 --, reacting a 
compound of formula Ar.sup.2 --Ar.sup.1 --CH.sub.2 --M in which M is a 
metal atom or a derivative thereof, with a compound of formula VIII. 
Suitable values for M and suitable reaction conditions are those mentioned 
in (d) above. The compounds of formula Ar.sup.2 --Ar.sup.1 --CH.sub.2 --M 
may be prepared from the corresponding halogeno compound in a manner 
analogous to the preparation of compounds of formula Ar.sup.2 --Ar.sup.1 
--M discussed in (d) above. 
j) For those compounds of formula I in which X is --CH.sub.2 O-- or 
--CH.sub.2 S-- and R.sup.1 and R.sup.2 are hydrogen, reacting a compound 
of formula Ar.sup.2 --Ar.sup.1 --CH.sub.2 --Z.sup.1 with a compound of 
formula IX, in which Z.sup.1 is a leaving group and Z.sup.2 is --YM, or 
Z.sup.1 is --YM and Z.sup.2 is a leaving group, and wherein Y is oxygen or 
sulphur (as appropriate) and M is a metal atom. 
Suitable leaving groups include, for example, halogen (such as chloro, 
bromo or iodo), methanesulphonyloxy, toluenesulphonyloxy or 
trifluoromethanesulphonyloxy; and suitable metals include, for example 
sodium and lithium. 
The process is generally performed in the presence of a suitable solvent, 
for example, a hydrocarbon, such as toluene or xylene, or an ether such as 
dioxan or tetrahydrofuran, and at a temperature in the range, for example 
20.degree.-150.degree. C. 
It may be desirable to protect the quinuclidine nitrogen atom during the 
reaction, especially when Z.sup.1 is --YM, as described in (l) below. It 
may be desirable to protect R.sup.1 when it represents a hydroxy group as, 
for example, a silyl ether. 
k) For those compounds of formula I in which X is --CH.sub.2 O-- or 
--CH.sub.2 S-- and R.sup.1 and R.sup.2 are both hydrogen, reacting a 
compound of formula Ar.sup.2 --Ar.sup.1 --YH in which Y is oxygen or 
sulphur as appropriate with a compound of formula X in which Z is a 
leaving group. 
Suitable leaving groups include halogen, such as chloro, bromo or iodo, 
methanesulphonyloxy and toluenesulphonyloxy. The reaction is generally 
carried out in the presence of a base such as an alkali metal hydroxide, 
e.g. sodium or potassium hydroxide, and in a solvent such as 
dimethylsulphoxide or dimethylformamide. 
l) For compounds of formula I in which X is --OCH.sub.2 --, --SCH.sub.2 --, 
--CH2O--, or --CH.sub.2 S--, deprotecting a compound of formula XI in 
which Q is a protecting group, R1 is hydrogen or hydroxy and R2 is 
hydrogen. 
Suitable values for Q include, for example, --BH.sub.3 or an oxygen atom. 
When Q is --BH.sub.3 the deprotection may be carried out by treatment with 
an acid such as hydrochloric acid in a solvent such as acetone. When Q is 
an oxygen atom deprotection may be carried out by reduction using a 
suitable reducing agent such as sulphur dioxide. 
The compounds of formula XI in which X is --CH.sub.2 O-- or --CH.sub.2 S-- 
may be prepared by methods analogous to those described in (j), and in 
which X is --OCH.sub.2 -- or --SCH.sub.2 -- by methods analogous to those 
described in (k) above, but in which the starting material containing the 
quinuclidine moiety is protected by Q. A preferred way of preparing 
compounds of formula XI in which X is --CH.sub.2 O-- or --CH.sub.2 S-- and 
R.sup.1 is hydroxy and R.sup.2 is hydrogen is by a procedure analogous to 
that described in (f) in which the compound of formula VI is protected by 
Q. The quinuclidine moiety in the various starting materials may be 
protected using methodology well known in the art. Thus, for example, 
those in which Q is BH.sub.3 may be prepared by reaction of the 
appropriate quinuclidine moiety with BH.sub.3.THF, generally with cooling 
(for example at -70.degree. C.); whilst those in which Q is an oxygen atom 
may be prepared by oxidation of the appropriate quinuclidine moiety with, 
for example, 30% hydrogen peroxide. 
m) For those compounds of formula I in which X is --C.tbd.C--, reacting a 
compound of formula I in which X is --CH.dbd.CH-- with a halogen, followed 
by treatment with a base. 
A suitable halogen is bromine and the reaction is conveniently carried out 
in an inert solvent such as carbon tetrachloride. Suitable bases include, 
for example, potasium t-butoxide. This treatment is conveniently carried 
out in a solvent such as THF, with heating (e.g. at a temperature between 
ambient and about 70.degree. C.). 
n) For those compounds of formula I in which R.sup.1 is hydroxy, R.sup.2 is 
hydrogen and X is --C.tbd.C--, reacting a compound of formula Ar.sup.2 
--Ar.sup.1 --C.tbd.C--M in which M is a metal atom, with 
quinuclidin-3-one. 
A suitable metal is lithium and suitable reaction conditions include those 
mentioned in (d) above. 
o) For those compounds in which R.sup.1 and R.sup.2 are hydrogen and X is 
--C.tbd.C--, reacting a compound of formula Ar.sup.2 --Ar.sup.1 
--C.tbd.C--M in which M is a metal atom with a compound of formula IX in 
which Z is a leaving group and R.sup.1 and R.sup.2 are hydrogen. 
Suitable values for Z include, for example, halogen (such as chloro, bromo 
or iodo), methanesulphonyloxy, toluenesulphonyloxy or 
trifluoromethanesulphonyloxy; suitable values for M include, for example, 
lithium; and suitable reaction conditions include those mentioned under 
(d) above. 
p) For those compounds in which X is --C.tbd.C-- and R.sup.1 is hydrogen or 
hydroxy and R.sup.2 is hydrogen, reacting a compound of formula XII in 
which R.sup.1 is hydrogen or hydroxy and R.sup.2 is hydrogen with a 
compound of formula Ar.sup.2 --Ar.sup.1 --Z in which Z is a leaving group 
in the presence of a catalyst. 
Suitable catalysts include, for example, transition metal complexes such as 
palladium or nickel complexes. Particular catalysts are palladium (II) 
complexes, a specific example of which is Pd(PPh.sub.3).sub.2 Cl.sub.2. 
Suitable values for Z include, for example, halogen (such as chloro, bromo 
or iodo), methanesulphonyloxy, toluenesulphonyloxy and 
trifluoromethanesulphonyloxy. The reaction is generally carried out in the 
presence of a base, for example, an amine such as triethylamine and in a 
solvent such as dimethylformamide with heating (for example at 60.degree. 
to 100.degree. C.). The reaction is preferably carried out in the 
prersence of copper(I)iodide. Compounds of formula XII may be prepared 
according to Scheme 1a and 2b. 
q) For those compounds in which X is --C.dbd.C-- and R.sup.1 is hydrogen or 
hydroxy and R.sup.2 is hydrogen, reacting a compound of formula XIII in 
which R.sup.1 is hydrogen or hydroxy and R.sup.2 is hydrogen with a 
compound of formula Ar.sup.2 --Ar.sup.1 --Z in which Z is a leaving group 
in the presence of a catalyst. 
Suitable reaction conditions are those mentioned under (p) above. Compounds 
of formula XIII may be prepared according to Scheme 1b and 2a. 
r) For those compounds of formula I in which R.sup.1 is hydrogen or hydroxy 
and R.sup.2 is hydrogen, reacting a compound of formula Ar.sup.2 M wherein 
M is a metal atom or a metal atom having suitable ligands with a compound 
of formula XIV wherein Z is a leaving group, in the presence of a 
catalyst. 
Suitable values for Z include, for example, halogen such as bromo or iodo, 
and a trifluoromethanesulphonyloxy group. Suitable values for the metal 
atom include, for example, copper and lithium. Suitable values for a metal 
atom having suitable ligands include, for example, those which contain a 
tin, boron, silicon, zirconium, aluminium, magnesium or mercury atom. 
Suitable ligands include, for example, alkyl groups (such as methyl, 
ethyl, propyl or butyl); halogen (such as fluoro, bromo or iodo); and 
hydroxy. Particular ligands include, for example, for tin, three 
substituents independently selected from (1-6C)alkyl (such as methyl, 
ethyl, propyl or butyl); for silicon a substituent selected from methyl 
and fluoro together with two fluoro atoms; for zirconium atom a halogeno 
group (such as fluoro, chloro, bromo or iodo) and two cyclopentadienyl 
radicals; for aluminium, two groups independently selected from 
(1-6C)alkyl (such as methyl, ethyl, propyl or butyl); for mercury atom a 
single group selected from a halogeno (such as fluoro, chloro, bromo or 
iodo), trifluoroacetyloxy or acetyloxy group; for magnesium, a halogeno 
group (such as fluoro, chloro, bromo or iodo); and for boron two groups 
independently selected from hydroxy, (1-4C)alkoxy (such as methoxy or 
ethoxy) and (1-6C)alkyl (such as methyl, ethyl, propyl or butyl). In the 
case of boron, the groups may, together with the boron atom to which they 
are attached, form a boroxin ring. 
A particularly suitable value for a metal atom having suitable ligands is 
the group --B(OH).sub.2. 
Suitable catalysts include, for example, a catalyst selected from a 
palladium (0), palladium (II), nickel (0) and nickel (II) catalyst. 
Particular catalysts include, for example, 
tetrakis-(triphenylphosphine)nickel(0), bis(triphenylphosphine)nickel(II) 
chloride, nickel(II)chloride, palladium(II)chloride, 
bis(triphenylphosphine)palladium(II)chloride, 
bis(triphenylphosphine)phenylpalladium iodide and 
tetrakis(triphenylphosphine)palladium(0). A radical initiator, for 
example, azo(bisisobutyronitrile) may also be present. 
The process is generally performed in the presence of a suitable solvent or 
diluent, for example, a hydrocarbon, such as toluene or xylene, or an 
ether such as dioxan or tetrahydrofuran, and at a temperature in the 
range, for example, 20.degree.-150.degree. C. 
Compounds of the formula Ar.sup.2 M are known or may be obtained by analogy 
therewith or, for example, by reaction of a compound of the formula M.Hal 
wherein M is the metal atom (defined above) and Hal is a halogeno group 
such as chloro, bromo or iodo, with a Grignard reagent or aryllithium 
compound derived, using standard procedures, from a compound of the 
formula Ar.sup.2 -hal wherein hal is a halogeno group such as chloro, 
bromo or iodo. The reaction is generally carried out in a solvent such as 
tetrahydrofuran or ether, or a mixture thereof, and at a temperature of 
-78.degree. C. to 25.degree. C. In the case where the group which 
comprises a boron atom having ligands selected from alkoxy and hydroxy, 
the compounds of formula Ar.sup.2 M may also be prepared by reaction of a 
trialkylboronate of the formula B(OR).sub.3 wherein R is a (1-6C)alkyl 
group with a Grignard reagent or aryllithium compound derived, using 
standard procedures, from a compound of the formula Ar.sup.2 -hal wherein 
hal is a halogeno group such as chloro, bromo or iodo. The reaction is 
generally carried out in a solvent such as tetrahydrofuran or ether, or a 
mixture thereof, and at a temperature of -78.degree. C. to 25.degree. C. 
The compounds of formula Ar.sup.2 M wherein the ligands attached to boron 
are alkoxy can be converted to those in which the ligands are hydoxy using 
standard techniques. The boroxin derivatives may be prepared from the 
latter compounds by dehydration using standard procedures. 
Compounds of formula XIV may be prepared using analogous methods to those 
described above for the preparation of compounds of formula I. 
s) For those compounds of formula I in which R.sup.1 is hydrogen or hydroxy 
and R.sup.2 is hydrogen, reacting a compound of formula XV wherein M is a 
metal atom or a metal atom having suitable ligands with a compound of 
formula Ar.sup.2 Z wherein Z is a leaving group, in the presence of a 
catalyst. 
Suitable values for M and Z and reaction conditions are those mentioned 
above (r). 
Compounds of formula Ar.sup.2 Z are readily available or may be prepared by 
methods well known in the art. Compounds of formula XV may be readily 
prepared by methods well known in the art, for example by from compounds 
of formula XIV in an analogous manner to the preparation of compounds of 
formula Ar.sup.2 M described above. 
The various starting materials referred to in (a) to (s) above are readily 
available or may be prepared by methods well known on the art. For 
example, starting materials having the bi-aryl ring system Ar.sup.2 
--Ar.sup.1 may be prepared by coupling the appropriately substituted rings 
Ar.sup.2 and Ar.sup.1 using a procedure analogous to that described in (r) 
and (s) above. Thus, for example, Ar.sup.2 --Ar.sup.1 -hal used in (d) 
above may be prepared by reaction of a compound of formula Ar.sup.2 --M 
(wherein M is a metal or a metal having suitable ligands) with a compound 
of formula Z--Ar.sup.1 -"hal" (wherein Z is a leaving group) in the 
presence of a catalyst as described in (r) below, or by the reaction of a 
compound of formula M--Ar.sup.1 -hal with a compound of formula Ar.sup.2 
--Z as described in (s) below. 
t) For those compounds of formula I in which X is --CH.dbd.CH--, reacting a 
compound of formula XVI in which L is a suitable ligand with a compound of 
formula Ar.sup.2 --Ar.sup.1 --Z in which Z is a leaving group in the 
presence of a catalyst. 
Suitable values for L include, for example, (1-6C)alkyl with butyl being 
preferred. Suitable values for Z, suitable catalysts and reaction 
conditions include those mentioned under (r) above. A particularly 
suitable catalyst is, for example, tris(dibenzylideneacetone)palladium 
0!. 
It will be appreciated that in some of the reactions mentioned herein it 
may be necessary/desirable to protect any sensitive groups in the 
compounds. The instances where protection is necessary or desirable and 
suitable methods for protection are known to those skilled in the art. 
Thus, if reactants include groups such as amino, carboxy or hydroxy it may 
be desirable to protect the group in some of the reactions mentioned 
herein. Suitable protecting groups for hydroxy include, for example, silyl 
groups such as trimethylsilyl or t-butyldimethylsilyl, tetrahydropyranyl 
and esterifing groups such as a methyl or ethyl ester; and for amino 
groups include benzyloxycarbonyl and t-butoxycarbonyl. Carboxy groups may 
be protected in a reduced form such as in the form of the corresponding 
protected alcohol, which may be subsequently oxidised to give the carboxy 
group. The protecting groups may be removed at any convenient stage in the 
synthesis using conventional techniques well known in the chemical art. 
It will also be appreciated that the preferred process for preparing a 
particular compound of formula I will depend upon the nature of the 
various radicals. Similarly, the preferred choice of reagent will depend 
upon the nature of the various radicals present. For example, when it is 
required to reduce a particular compound the reducing agent will generally 
be selected to be one which does not interfere with other groupings 
present. 
It will also be appreciated that certain of the various optional 
substituents in the compounds of the present invention may be introduced 
by standard aromatic substitution reactions or generated by conventional 
functional group modifications either prior to or immediately following 
the processes mentioned above, and as such are included in the process 
aspect of the invention. Such reactions and modifications include, for 
example, introduction of a substituent by means of an aromatic 
substitution reaction, reduction of substituents, alkylation of 
substituents and oxidation of substituents. The reagents and reaction 
conditions for such procedures are well known in the chemical art. 
Particular examples of aromatic substitution reactions include the 
introduction of a nitro group using concentrated nitric acid, the 
introduction of an acyl group using, for example, an acylhalide and Lewis 
acid (such as aluminium trichloride) under Friedel Crafts conditions; the 
introduction of an alkyl group using an alkyl halide and Lewis acid (such 
as aluminium trichloride) under Friedel Crafts conditions; and the 
introduction of a halogeno group. Particular examples of modifications 
include the reduction of a nitro group to an amino group by for example, 
catalytic hydrogenation with a nickel catalyst or treatment with iron in 
the presence of hydrochloric acid with heating; oxidation of alkylthio to 
alkylsulphinyl or alkylsulphonyl. 
It will be appreciated that when a pharmaceutically acceptable salt is 
required it may be prepared by reacting the compound of formula I with an 
acid which affords a physiologically acceptable anion or a base which 
affords a physiologically acceptable cation, or by any other conventional 
salt formation process. 
As mentioned previously, the compounds of the formula I (and their 
pharmaceutically-acceptable salts) are inhibitors of the enzyme squalene 
synthase. Thus the compounds of the present invention are capable of 
inhibiting cholesterol biosynthesis by inhibition of de novo squalene 
production. 
The beneficial pharmacological properties of the compounds of the present 
invention may be demonstrated using one or more of the following 
techniques. 
(a) Inhibition of Squalene synthase 
In this test, the ability of a compound to prevent the formation of 
squalene from a radioactive substrate (tritiated farnesyl pyrophosphate) 
is assessed. 
The test compound is incubated at a concentration of 25 micromolar in 200 
.mu.l of a buffered solution containing potassium phosphate (50 mM), 
MgCl.sub.2 (4.95 mM), KF (9.9 mM), NADPH (0.9 mM) and rat liver microsomal 
protein (20 .mu.g). Rat liver microsomes are prepared by the method 
described in published European Patent Application No. 324,421 and stored 
in liquid nitrogen prior to assay. Assay vials are kept at 37.degree. C. 
throughout the incubation. 
The reaction is started with the addition of the substrate (1-.sup.3 
H!-farnesyl pyrophosphate), final concentration 20 .mu.M, and stopped 
after 15 minutes reaction time with the addition of 50 .mu.l of 4% KOH. 
The reaction products are separated from unreacted substrate after 
application to a C-18 octadecyl 1 ccBond column (Analytichem Int product 
No. 617101). An aqueous fraction is eluted with 250 .mu.l of 0.1M KOH. 
Squalene is then eluted with 1.0 ml 10% ethylacetate in hexane and 
radioactivity determined. The difference in radioactivity in the presence 
and absence of the test compound is used to determine the level of 
inhibition. If the test compound inhibits at greater than about 70% at 25 
micromolar, it is generally re-tested at 25 and 2.5 micromolar. The 
IC.sub.50 (concentration which results in a 50% inhibition of squalene 
production), of the test compound can be determined by testing the 
compound at several, for example five, concentrations predicted from the 
two concentration results. The IC.sub.50 can then be determined from a 
plot of percentage inhibition against concentration of test compound. 
In general, compounds of formula I show significant inhibition in the above 
test at a concentration in the range of about 0.001 to 25 .mu.M. 
By way of illustration of the squalene synthase inhibitory properties of 
the compounds of formula I, the compound of formula I described in Example 
2 below gave about 98% inhibition at 2.5 .mu.M. 
(b) Acute rat cholesterol synthesis assay. 
This is an acute in vivo test in the rat to measure de novo hepatic 
cholesterol synthesis from exogenously administered .sup.14 C-acetate. 
Female rats (35-55 g) are housed in reverse lighting conditions (red light 
from 0200 h-1400 h) for a period of about 2 weeks prior to test. Animals 
are allowed free access to chow and drinking water throughout this period. 
At test, animals should weigh 125-150 g. 
Test compounds may be administered by oral gavage, dissolved or suspended 
in 0.5% polysorbate, or by ip or iv dosing. Control animals receive 
vehicle alone. After 1 hour the rats are injected ip with 25 .mu.Ci 
2-.sup.14 C!-acetate (NEN DUPONT, specific activity, 45-60 mCi/mmol 
NEC-085H, or AMERSHAM specific activity, 50-60 mCi/mmol CFA 14) in a 
volume of 0.25 ml saline (100 .mu.Ci/ml). After a further hour, rats are 
terminally anaesthetised with halothane and a blood sample obtained from 
the abdominal vena cava. 
1 ml of plasma is lyophilised and then saponified in 2 ml ethanolic KOH (1 
part 33% KOH, 9 parts ethanol) at 75.degree. C. for 2 hours. After 
addition of an equal quantity of water, non-saponifiable lipids are 
extracted with two 5 ml volumes of hexane. The hexane extracts are 
evaporated to dryness and the residues dissolved in ethanol to determine 
cholesterol specific radioactivity. ED.sub.50 values can be determined in 
the standard way. 
In general, compounds of formula I show activity in the range of about 0.1 
to 100 mg/kg. 
By way of illustration, the compound of formula I described in Example 2 
gave an ED.sub.50 of 8 mg/kg. 
No overt toxicity was detected when compounds of the formula I were 
administered at several multiples of their minimum inhibitory dose or 
concentration. 
As mentioned above, the compounds of the present invention are squalene 
synthase inhibitors and hence possess the property of inhibiting 
cholesterol biosynthesis. Thus the compounds of the present invention will 
be useful in treating diseases or medical conditions in which an 
inhibition of squalene synthase is desirable, for example those in which a 
lowering of the level of cholesterol is blood plasma is desirable. In 
particular, the compounds of the present invention will be useful in 
treating hypercholesterolemia and/or ischaemic diseases associated with 
atheromatous vascular degeneration such as atherosclerosis. The compounds 
of the present invention will also be useful in treating fungal 
infections. 
Thus according to a further feature of the present invention there is 
provided a method of inhibiting squalene synthase in a warm-blooded 
animals (such as man) requiring such treatment, which method comprises 
administering to said animal an effective amount of a compound of formula 
I (as herein defined), or a pharmaceutically-acceptable salt thereof. In 
particular, the present invention provides a method of inhibiting 
cholesterol biosynthesis, and more particularly to a method of treating 
hypercholesterolemia and atheromatous vascular degeneration (such as 
atherosclerosis). 
Thus the present invention also provides the use of a compound of formula I 
(as herein defined), or a pharmaceutically-acceptable salt thereof, for 
the manufacture of a medicament for treating diseases or medical 
conditions in which a lowering of the level of cholesterol in blood plasma 
is desirable (such as hypercholesterolemia and atherosclerosis). 
When used in the treatment of diseases and medical conditions in which an 
inhibition of cholesterol biosynthesis is desired, for example in the 
treatment of hypercholesterolemia or atherosclerosis, it is envisaged that 
a compound of formula I (or a pharmaceutically acceptable salt thereof) 
will be administered orally, intravenously, or by some other medically 
acceptable route so that a dose in the general range of, for example, 0.01 
to 50 mg per kg body weight is received. However it will be understood 
that the precise dose administered will necessarily vary according to the 
nature and severity of the disease, the age and sex of the patient being 
treated and the route of administration. 
In general, the compounds of formula I (or a pharmaceutically-acceptable 
salt thereof) will usually be administered in the form of a pharmaceutical 
composition, that is together with a pharmaceutically acceptable diluent 
or carrier, and such a composition is provided as a further feature of the 
present invention. 
A pharmaceutical composition of the present invention may be in a variety 
of dosage forms. For example, it may be in the form of tablets, capsules, 
solutions or suspensions for oral administration, in the form of a 
suppository for rectal administration; in the form of a sterile solution 
or suspension for parenteral administration such as by intravenous or 
intramuscular injection. 
A composition may be obtained by conventional procedures using 
pharmaceutically acceptable diluents and carriers well known in the art. 
Tablets end capsules for oral administration may conveniently be formed 
with a coating, such as an enteric coating (for example, one based on 
cellulose acetate phthalate), to minimise dissolution of the active 
ingredient of formula I (or a pharmaceutically-acceptable salt thereof) in 
the stomach or to mask unpleasant taste. 
The compounds of the present invention may, if desired, be administered 
together with (or sequentially to) one or more other pharmacological 
agents known to be useful in the treatment of cardiovascular disease, for 
example, together with agents such as HMG-CoA reductase inhibitors, bile 
acid seguestrants, other hypocholesterolaemic agents such as fibrates, for 
example gemfibrozil, and drugs for the treatment of coronary heart 
disease. As a further example, the compounds of the present invention may, 
if desired, be administered together with (or sequentially to) an 
angiotensin converting enzyme (ACE) inhibitor, such as captopril, 
lisinopril, zofenopril or enalapril. 
The compounds of the present invention may also find utility as antifungal 
agents, and so the present invention also provides a method of treating 
fungal infections which comprises administration to an a warm blooded 
animal, such as man, in need of such treatment an effective amount of a 
compound of formula I, or a pharmaceutically acceptable salt thereof. When 
used in this way the compounds of the present invention may, in addition 
to the formulations mentioned above, be adapted for topical administration 
and such a composition is provided as a further feature of the present 
invention. Such compositions may be in a variety of forms, for example 
creams or lotions.

The invention will now be illustrated by the following non-limiting 
Examples in which, unless otherwise stated: 
(i) evaporations were carried out by rotary evaporation in vacuo; 
(ii) operations were carried out at room temperature, that is in the range 
18.degree.-26.degree. C.; 
(iii) flash column chromatography or medium pressure liquid chromatography 
(MPLC) was performed on silica gel (Merck Kieselgel Art.9385, obtained 
from E Merck, Darmstadt, Germany); 
(iv) yields are given for illustration only and are not necessarily the 
maximum attainable by diligent process development; 
(v) proton NMR spectra were normally determined at 200 MHz in a solvent of 
DHSOd.sub.6 using tetramethylsilane (TMS) as a internal standard, and are 
expressed as chemical shifts (delta values) in parts per million relative 
to TMS using conventional abbreviations for designation of major peaks: s, 
singlet; m, multipier; t, triplet; br, broad; d, doublet; 
(vi) all end-products were characterised by microanalysis, NMR and/or mass 
spectroscopy (molecular ions denoted by m/z); and 
(vii) conventional abbreviations are used for individual radicals and 
recrystallisation solvents, for example, Me=methyl, Et=ethyl, Pr=Propyl, 
Pr.sup.i =isopropyl, Bu=butyl, Bu.sup.i =isobutyl, Ph=phenyl; EtOAc=ethyl 
acetate, Et.sub.2 O=ether, MeCN=acetonitrile, MeOH=methanol, EtOH=ethanol, 
Pr.sup.i OH=2-propanol, H.sub.2 O=water. 
EXAMPLE 1 
A mixture of 3-(4-bromophenyl)pyridine (1.17 g), 
3-ethynyl-3-hydroxyquinuclidine (750 mg), 
bis(triphenylphosphine)-palladium (II) chloride (175 mg), copper (I) 
iodide (88 mg), triethylamine (5.0 ml) and dimethylformamide (10 ml) was 
stirred at 70.degree. C. under an atmosphere of argon for 5 hours. The 
triethylamine and dimethylformamide were removed by evaporation. A 2M 
aqueous solution of sodium hydroxide (10 ml) was added to the residue and 
the mixture extracted with dichloromethane (3.times.10 ml). The organic 
extracts were combined, dried (MgSO.sub.4) and evaporated to give a solid 
residue. 
This residue was purified by flash chromatography using a mixture of 10% 
methanol in dicbloromethane containing 1% 0.880 ammonia as eluent to give 
3-2-(4-3-pyridyl!phenylethynyl)-3-hydroxyquinuclidine (340 mg), m.p. 
189.degree.-190.degree. C.; microananlysis, found: C, 77.5; H, 6.5; N, 
9.2%; C.sub.20 H.sub.20 N.sub.2 0.0.25H.sub.2 O requires: C, 77.8; H, 
6.64; N, 9.08%; NMR (DMSO-d.sub.6); 1.2-1.45(1H, m), 1.5-1.7(1H, m), 
1.8-2.0(3H, m), 2.7(4H, m), 2.9(1H, d), 3.15(1H, d), 5.65(1H, s), 7.5(3H, 
m), 7.75(2H, d), 8.1(1H, m), 8.6(1H, m) and 8.9(1H, m); m/Z 305 (M+H). 
The 3-ethynyl-3-hydroxyquinuclidine used as starting material was obtained 
as follows: 
A solution of n-butyl lithium (100 ml of a 2M solution in pentane) was 
added portion-wise over a period of 20 minutes to a stirred solution of 
ethynyltrimethylsilane (19.6 g) in dry tetrahydrofuran (400 ml) at 
-70.degree. C. The mixture was stirred for 1 hour at -70.degree. C. A 
solution of 3-quinuclidone (2.4 g) in dry tetrahydrofuran (100 ml) was 
then added to the mixture and the mixture stirred for 1 hour at 
-70.degree. C. Methanol (1 ml) was then added to the mixture and the 
mixture allowed to warm to room temperature. The solvents were removed by 
evaporation. Methanol (500 ml) and potassium carbonate (40 g) were added 
to the residue and the mixture was stirred for 1 hour. The solvent was 
removed by evaporation. The residue was triturated with water (500 ml) and 
the solid obtained dried in vacuo. There was thus obtained 
3-ethynyl-3-hydroxy-quinuclidine as a solid, m.p. 193.degree.-197.degree. 
C.; NMR (DMSO-d.sub.6): 1.5-1.3(1H, m), 1.4-1.6(1H, m), 1.7-1.95(3H, m), 
2.55-2.8(5H, m), 2.95(1H, d), 3.3(1H, d) and 5.4(1H, s); m/Z 152 (M+H). 
The 3-(4-bromophenyl)pyridine used as starting material was obtained as 
follows: 
A solution of 4-bromobenzeneboronic acid (6.0 g) in absolute ethanol (15 
ml) was added slowly to a stirred mixture of a solution of 3-bromopyridine 
(4.7 g) in toluene (30 ml), a saturated aqueous solution of sodium 
carbonate (10 ml) and tetrakistriphenylphosphine palladium 0! (1.0 g) 
under an atmosphere of argon. The mixture was then heated to reflux and 
stirred at reflux under an atmosphere of argon for 6 hours. The mixture 
was cooled and water (50 ml) added. The resulting mixture was extracted 
with ethyl acetate (3.times.30 ml). The ethyl acetate extracts were 
combined, and then extracted with 2N aqueous hydrochloric acid (3.times.20 
ml). The acidic extracts were combined, cooled by the addition of ice and 
basified by the addition of sodium hydroxide solution to give a pH of 9. 
The mixture was then extracted with ethyl acetate (3.times.30 ml). These 
ethyl acetate extracts were combined, dried (MgSO.sub.4) and evaporated to 
afford 3-(4-bromophenyl)pyridine as a colourless oil (1.2 g); NMR 
(CDCl.sub.3): 7.3-7.5(3H, m), 7.6(2H, d), 7.85(1H, d of t), 8.6(1H, d of 
d) and 8.8(1H, d). 
EXAMPLE 2 
A mixture of 3-ethynyl-3-hydroxyquinuclidine (516 mg), 
2-(4-bromophenyl)pyridine (400 mg), bis(triphenylphosphine)palladium (II) 
chloride (100 mg), copper(I) iodide (50 mg) triethylamine (15 ml) and 
dimethylformamide (10 ml) was stirred at 90.degree. C. under an atmosphere 
of argon for 2.5 hours. The mixture was allowed to cool to room 
temperature, alumina (5 g) added and the solvents removed by evaporation. 
This pre-absorbed material was chromatographed on alumina (30 g) using a 
mixture of 10% ethanol in ethyl acetate as eluent. There was thus obtained 
a residue which was crystallised from ethanol/hexane to give 
3-2-(4-2-pyridyl!phenyl)ethynyl!-3-hydroxyquinuclidine as a solid, m.p. 
205.degree.-206.degree. C.; microanalysis, found: C, 77.7; H, 6.4; N, 
9.0%; C.sub.20 H.sub.2 ON.sub.2 O.0.25H.sub.2 O requires: C, 77.8; H, 6.5; 
N, 9.08%; NMR (DMSO-d.sub.6): 1.3(1H, m), 1.6(1H, m), 1.8-2.0(3H, m), 
2.7(4H, m), 2.85(1H, d), 3.1(1H, d), 5.6(1H, s), 7.4(1H, m), 7.5(2H, d), 
7.85-8.05(2H, m), 8.1(1H, d) and 8.7(1H, d); m/Z 305 (M+H). 
The 2-(4-bromophenyl)pyridine used as starting material was obtained using 
the procedure described in Example 1 for the preparation of 
3-(4-bromophenyl)pyridine, but using 2-bromopyridine in place of 
3-bromopyridine. There was thus obtained 2-(4-bromophenyl)pyridine as an 
oil, NMR (CDCl.sub.3): 7.25(1H, m), 7.6(2H, d), 7.7-7.8(2H, m), 7.9(1H, 
d), 8.5(1H, d of d). 
EXAMPLE 3 
A mixture of 3-ethynyl-3-hydroxyquinuclidine (302 mg), 
4-(1-imidazolyl)phenyl triflate (584 mg), 
bis-(triphenylphosphine)-palladium (II) chloride (140 mg), copper (I) 
iodide (70 mg), triethylamine (5 ml) and dimethylformamide (10 ml) was 
stirred at 90.degree. C. under an atmosphere of argon for 6 hours. The 
mixture was evaporated and the residue purified by flash chromatography 
using a gradient of 10% methanol in dichloromethane containing 1% 0.880 
ammonia to 15% methanol in dichloromethane containing 1% 0.880 ammonia as 
eluent to give a residue which was further purified by reverse phase 
preparative HPLC, using a mixture of 80% aqueous methanol containing 0.5% 
triethylamine as eluent. There was thus obtained 
3-2-(4-1-imidazolyl!phenyl)ethynyl!-3-hydroxyquinuclidine (70 mg) as a 
solid, m.p. 236.degree.-240.degree. C.; microanalysis, found: C, 72.8; H, 
6.5; N, 13.8%; C.sub.18 H.sub.19 N.sub.3 O.0.25H.sub.2 O requires: C, 
72.6; H, 6.55; N, 14.1%; NMR (DMSO-d.sub.6): 1.2-1.4(1H,m), 1.5-1.7(1H, 
m), 1.8-2.02(3H, m), 2.6-2.8(4H, m), 2.85(1H,d), 3.1(1H,d), 5.65(1H,s), 
7.1(1H,s), 7.5-7.6(2H,m), 7.62-7.7(2H, m), 7.8(1H, s) and 8.3(1H, s); m/Z 
294 (M+H). 
The 4-(1-imidazolyl)phenyl triflate used as starting material was obtained 
as follows: 
Triflic anhydride (2.82 g) was added dropwise to a mixture of 
4-(1-imidazolyl)phenol (Aldrich Chemical Company) and triethylamine (1.1 
g) in dichloromethane (30 ml). The mixture was stirred for 18 hours. The 
mixture was evaporated and the residue partitioned between diethyl ether 
and water. The organic phase was separated, washed with water, dried 
(MgSO.sub.4) and evaported. The residue was triturated with cyclohexane to 
give crude 4-(1-imidazolyl)phenyl triflate (1.7 g) as a solid, which was 
used without further purification; m/Z 293 (M+H). 
EXAMPLE 4 
A mixture of 3-ethenyl-3-hydroxyquinuclidine (673 mg), 
3-(4-bromophenyl)pyridine (1.08 g), bis-(triphenylphosphine)-palladium 
(II) chloride (140 mg), copper (I) iodide (70 mg), and dimethylformamide 
(10 ml) was stirred at 130.degree. C. under an atmosphere of argon for 4 
hours. The mixture was evaporated and the residue was paritioned between 
aqueous 2M sodium hydroxide solution (10 ml) and dichloromethane (10 ml). 
The organic layer was separated, washed with dichloromethane (2.times.10 
ml), dried (MgSO.sub.4) and evaporated. The residue was crystallised from 
acetonitrile to give 
3-2-(4-3-pyridyl!phenyl)ethenyl!-3-hydroxyquinuclidine (400 mg) as a 
solid, m.p. 195.degree.-198.degree. C.; microanalysis, found: C, 76.4; H, 
7.2; N, 8.6%; C.sub.20 H.sub.22 N.sub.2 O.0.5H.sub.2 O requires: C, 76.2; 
H, 7.3; N, 8.9%; NMR (DMSO-d.sub.6 +CD.sub.3 COOD): 1.7-2.15(4H, m), 
2.35(1H, m), 3.15-3.4(5H, m), 3.5(1H, d), 6.7(1H, d), 6.9(1H, d), 
7.5-7.8(7H, m), 8.15(1H, d); m/Z 307 (M+H). 
The 3-ethenyl-3-hydroxyquinuclidine used as starting material was prepared 
as follows: 
A mixture of 3-ethynyl-3-hydroxyquinuclidine (5.0g), palladium on calcium 
carbonate (5% w/w, 0.5 g) and ethanol (200 ml) was stirred under an 
atmosphere of hydrogen until 900 ml of hydrogen has been consumed. The 
mixture was filtered and evaporated to give 
3-ethenyl-3-hydroxyquinuclidine (5.0 g) as an oil which gave a solid on 
standing and was used without further purification, m.p. 
76.degree.-80.degree. C.; NMR(DMSO-d.sub.6): 1.2(1H, m), 1.4-1.6(3H, m), 
2.0(1H, m), 2.45-2.85(6H, m), 4.55(1H, s), 5.0(1H, d of d), 5.25(1H, d of 
d), 6.1(1H, d of d); m/z 154 (M+H). 
The 3-ethynyl-3-hydroxyquinuclidine was prepared as described in Example 1. 
EXAMPLE 5 
A mixture of 3-2-(4-3-pyridyl!phenyl)ethenyl!quinuclidine (153 mg), 
palladium-on-charcoal (10% w/w, 25 mg) and ethanol (20 ml) was stirred 
under an atmosphere of hydrogen until no further hydrogen uptake occured. 
The mixture was filtered and the filtrate was evaporated. This residue was 
treated with excess of a solution of hydrogen chloride in ether to give 
3-2-(4-3-pyridyl!phenyl)ethyl!-3-hydroxyrquinuclidine dihydrochloride as 
a solid (110 mg), m.p. 259.degree.-261.degree. C.; microanalysis, found: 
C, 60.7; H, 7.0; N, 6.7%; C.sub.20 H.sub.24 NO.sub.2.2HCl requires C, 
60.1; H, 7.0; N, 7.0%; NMR (DMSO-d.sub.6): 1.6-2.1(6H, m), 2.3(1H, m), 
2.7(2H, m), 3.0-3.3(6H, m), 7.45(2H, d), 7.8(2H, d), 8.0(1H, m), 8.65(1H, 
d), 8.8(1H, d) and 9.2(1H, m); m/Z 309 (M+H). 
EXAMPLE 6 
An ice-cooled solution of aqueous 3M hydrochloric acid (7.0 ml) in acetone 
(21.0 ml) was added to 
3-hydroxy-3-4-(3-pyridyl)phenoxymethyl!quinuclidine borane complex (1.4 
g). The latter dissolved immediately and the resulting colourless solution 
was stirred at 5.degree. C. for 1 hour during which a colourless 
precipitate formed. This solid was collected by filtration, washed with 
acetone and dried to afford crude product (1.02 g) which was 
recrystallised from ethanol (10 ml) to give 
3-hydroxy-3-4-(3-pyridyl)phenoxymethyl!quinuclidine dihydrochloride as a 
colourless solid (0.75 g), m.p. 263.degree.-265.degree. C.; microanalysis, 
found: C, 58.3; H, 6.7; N, 6.8%; C.sub.19 H.sub.22 N.sub.2 
O.sub.2.2HCl.0.4H.sub.2 O.0.3EtOH requires: C, 58.2; H, 6.6; N, 6.9%; NMR 
(DMSO-d.sub.6): 1.58-1.8(1H, m), 1.75-2.0(2H, m), 2.21(1H, s), 
2.95-3.4(6H, m), 4.15(2H, s), 7.16 and 7.85(4H, 2d), 8.02(1H,m), 8.77(2H, 
d), 9.18(1H, s), and 10.73(1H, s); m/z 311 (M+H). 
The 3-hydroxy-3-4-(3-pyridyl)phenyoxymethyl!quinuclidine borane complex 
used as starting material was obtained as follows. 
A solution of borane-tetrahydrofuran complex (135 ml of a 1M solution in 
tetrahydrofuran) was added portionwise over a period of 30 minutes to a 
stirred solution of 3-quinuclidinone (16.9 g) in dry tetrahydrofuran (300 
ml) at -70.degree. C. The mixture was stirred at -70.degree. C. for 30 
minutes. Water (20 ml) was added to the reaction mixture at -70.degree. C. 
The solvent was removed by evaporation. A saturated solution of brine (250 
ml) was added to the residue and the mixture was basified by addition of 
solid sodium carbonate. The mixture was extracted with dichloromethane 
(4.times.100 ml). The dichloromethane extracts were combined, silica gel 
(Merck 9385, 60 g) was added and the mixture was evaporated to give a free 
flowing powder. This pre-absorbed material on silica gel was purified by 
flash column chromatography on a further portion of silica gel using a 
mixture of 25% ethyl acetate/pentane as eluent to give 3-quinuclidinone 
borane complex (17.0 g) as a colourless solid, m.p. 
162.degree.-164.degree. C.; NMR (CDCl.sub.3): 0.7-2.3(3H, br), 2.0-2.3(4H, 
m), 2.7(1H, m), 3.0-3.4(4H, m) and 3.5(2H, s). 
Powdered trimethyl sulphoxonium iodide (24.4 g) was added portionwise to a 
stirred, ice-cooled, suspension of sodium hydride (60% w/w dispersion in 
mineral oil, 4.4 g; the oil was removed by washing the solid with 
petroleum ether) in dry dimethylformamide (140 ml) under an atmosphere of 
argon whilst maintaining the temperature at 10.degree. to 15.degree. C. 
The mixture was allowed to warm to room temperature. Solid 
3-quinuclidinone borane complex (15.5 g) was added to the stirred mixture 
whilst maintaining the temperature at 25.degree. to 30.degree. C. using an 
ice-bath. The mixture was then stirred at room temperature for 16 hours. 
The mixture was poured into water (1400 ml) and the mixture was extracted 
with ethyl acetate (4.times.400 ml). 
The ethyl acetate extracts were combined, washed with water (3.times.300 
ml), dried (Na.sub.2 SO.sub.4) and evaporated. The residue was purified by 
flash column chromatography on silica gel using dichloromethane as eluent 
to give 3-methylenequinuclidine oxide borane complex (13.8 g) as a 
colourless solid, m.p. 74.degree.-77.degree. C.; microanalysis, found: C, 
63.1; H, 10.6; N, 9.2%; C.sub.8 H.sub.16 BNO requires: C, 62.8; H, 10.5; 
N, 9.2%; NMR (CDCl.sub.3): 0.6-2.3(3H, br), 1.6(1H, m), 1.7-1.9(1H, m), 
1.9-2.0(2H, m), 2.1-2.3(1H, m), 2.8(2H, q) and 2.9-3.4(6H, m); m/z 152 
(M-H). 
Solid potassium carbonate (2.21 g) was added to a solution of 
4-(3-pyridyl)phenol (1.37 g) and 3-methylenequinuclidine oxide borane 
complex (1.22 g) in dry dimethylformamide (10 ml) under an atmosphere of 
argon. The mixture was stirred for 64 hours at room temperature followed 
by 3 hours at 70.degree. C. The mixture was poured into water (100 ml) and 
the mixture extracted with ethyl acetate (3.times.70 ml, 1.times.40 ml). 
The ethyl acetate extracts were combined, washed successively with water 
(3.times.60 ml) and aqueous 2M sodium hydroxide solution (1.times.60 ml, 
1.times.30 ml) and then extracted with aqueous 2M hydrochloric acid 
solution (2.times.50 ml, 1.times.30 ml). The acidic aqueous extracts were 
combined, washed with ethyl acetate (2.times.50 ml) and then basified by 
addition of solid sodium carbonate to precipitate an oil which was 
extracted with ethyl acetate (3.times.70 ml). The ethyl acetate extracts 
were combined, dried (Na.sub.2 SO.sub.4) and evaporated to give a yellow 
oil/foam (2.3 g) which, on trituration with ethyl acetate (10 ml), 
afforded a pale yellow solid (1.8 g). This solid was purified by flash 
chromatography using an eluent of ethyl acetate. There was thus obtained 
3-hydroxy-3-4-(3-pyridyl)phenoxymethyl!quinuclidine borane complex as a 
colourless solid (1.56 g), m.p. 157.degree.-159.degree. C.; microanalysis, 
found: C, 70.3; H, 8.0; N, 8.6; C.sub.19 H.sub.25 BN.sub.2 O.sub.2 
requires: C, 70.4; H, 7.8; N, 8.6%; NMR (DMSO-d.sub.6): 0.5-2.5(3H,br), 
1.53-1.75(1H, m), 1.73-1.95(2H, m), 2.23-2.48(2H, m), 2.8-3.3(6H, m), 
3.33(1H, br s), 3.93-4.12(2H, q), 7.00 and 7.5(4H, 2d), 7.35(1H, m), 
7.83(1H, m), 8.55(1H, d), 8.77(1H, s); m/z 323 (M-H). 
EXAMPLES 7-32 
Using a procedure similar to that described in Example 1, the following 
compounds of formula I, wherein Ar.sup.2 has the indicated values were 
prepared from the corresponding compounds of formula 2 (in which Z is 
bromo unless stated otherwise), with purification procedures and 
exceptions as noted. Where the compounds of formula 2 are not commercially 
available preparative details are given. 
EXAMPLE 7 
Ar.sup.2 =1-pyrrolyl 
Purified by flash column chromatography on silica gel using 10% methanol in 
dichloromethane containing 1% ammonia (density, 0.88 g/cm.sup.3) as eluent 
to give the title compound as a solid, m.p. 211.degree.-213.degree. C.; 
NMR: 1.2-1.4(1H,m), 1.5-1.7(1H,m), 1.8-2.0(3H,m), 2.6-2.8(4H,m), 
2.8-2.94(1H,d), 3.05-3.15(1H,d), 5.61(1H,s), 6.27(2H,m) and 
7.33-7.65(6H,m). 
EXAMPLE 8 
Ar.sup.2 =5-methyl-1,2,4-oxadiazol-3-yl 
Purified by crystallisation from acetonitrile to give the title compound as 
a solid, m.p. 214.degree.-215.degree. C.; NMR: 1.2-1.4(1H,m), 
1.5-1.7(1H,m), 1.8-2.0(3H,m), 2.6-2.8(4H,m), 2.66(3H,s), 2.8-2.9(1H,d), 
3.05-3.15(1H,d), 5.68(1H,s), 7.59(2H,d) and 7.99(2H,d). 
The compound of formula 2 (Z=iodo) was prepared as follows. 
A mixture of 4-iodobenzonitrile (7.69 g), anhydrous sodium carbonate (6.25 
g), hydroxylamine hydrochloride (8.74 g), in water (60 ml) and sufficient 
ethanol to maintain a clear solution, was heated at 90.degree.-100.degree. 
C. for 4 hours. The reaction mixture was cooled to ambient temperature and 
evaporated until a precipitate formed. The solid was collected by 
filtration, washed with water and recrystallised from acetonitrile to give 
4-iodobenzamidoxime (5.97 g), m.p. 155.degree.-161.degree. C.; 
microanalysis, found: C, 31.4; H, 2.7; N, 10.2%; C.sub.7 H.sub.7 IN.sub.2 
O 0.2H.sub.2 O requires: C, 31.6; H, 2.81; R, 10.5%; NMR: 5.82(2H,s), 
7.46(2H,d), 7.73(2H,d), 9.69(1H,s); m/z 263(M+H). 
Acetyl chloride (1.62 ml) was added to a solution of 4-iodobenzamidoxime 
(5.24 g) in pyridine (35 ml) at ambient temperature. The reaction mixture 
was heated at reflux for 3 hours. The mixture was cooled to ambient 
temperature, evaporated and ice-water was added to the residue. The solid 
was collected by filtration, washed with water and recrystallised from 
acetonitrile to give 3-(4-iodophenyl)-5-methyl-1,2,4-oxadiazole (4.43 g), 
m.p. 121.degree.-122.degree. C.; microanalysis found: C, 37.6; H, 2.4; N, 
9.7%; C.sub.9 H.sub.7 IN.sub.2 O requires: C, 37.8; H, 2.47; N, 9.79%; 
NMR: 2.66(3H,s), 7.77(2H,dd) and 7.94(2H,dd); m/z 287(M+H). 
EXAMPLE 9 
Ar.sup.2 =4-pyridyl 
Purified by flash column chromatography on silica gel using 10% methanol in 
dichloromethane containing 1% ammonia (density, 0.88 g/cm.sup.3) as 
eluent, followed by recrystallisation from acetonitrile, to give the title 
compound as a solid, m.p. 201.degree.-202.degree. C.; NMR: 1.2-1.4(1H,m), 
1.5-1.7(1H,m), 1.8-2.0(3H,m), 2.6-2.8(4H,m), 2.8-2.9(1H,d), 
3.05-3.15(1H,d), 5.63(1H,s), 7.55(2H,d), 7.73(2H,d), 7.83(2H,d) and 
8.64(2H,d). 
The compound of formula 2 used as starting material was prepared as 
follows. 
A solution of 4-bromobenzeneboronic acid (2 g) in absolute ethanol (10 ml) 
was added slowly to a stirred mixture of 4-bromopyridine hydrochloride 
(1.96 g) in toluene (10 ml), 2M aqueous sodium carbonate solution (25 ml) 
and tetrakistriphenylphosphine palladium 0! (345 mg) under an atmosphere 
of argon. The mixture was heated to reflux and stirred at reflux for 3 
hours. The mixture was cooled to ambient temperature and water (50 ml) was 
added. The resulting mixture was extracted with ethyl acetate (3.times.20 
ml). The ethyl acetate extracts were combined and extracted with 2N 
aqueous hydrochloric acid. The acidic extract was cooled and basified by 
the addition of aqueous sodium hydroxide solution to give a pH of 9. The 
mixture was then extracted with ethyl acetate (5.times.50 ml). The ethyl 
acetate extracts were combined, dried (MgSO.sub.4) and evaporated to give 
4-(pyrid-4-yl)bromobenzene as a solid (0.71 g), m.p. 
123.degree.-124.degree. C.; microanalysis, found: C, 56.4; H, 3.4; N, 
5.9%; C.sub.11 H.sub.8 BrN requires: C, 56.4; H, 3.4; N, 6.0%; m/z 
234(M+H). 
EXAMPLE 10 
Ar.sup.2 =5-pyrimidinyl 
Purified by flash chromatography on silica gel using 10% methanol in 
dichloromethane containing 1% ammonia (density, 0.88 g/cm.sup.3) as 
eluent, followed by recrystallisation from acetonitrile, to give the title 
compound as a solid, m.p. 218.degree.-219.degree. C.; NMR: 1.1-1.3(1H,m), 
1.38-1.57(1H,m), 1.66-1.9(3H,m), 2.5-2.65(4H,m), 2.66-2.8(1H,d), 
2.94-3.05(1H,d), 5.54(1H,s), 7.42(2H,d), 7.70(2H,d) and 9.01-9.06(3H,m). 
The compound of formula 2, 4-(pyrimidin-5-yl)bromobenzene, used as starting 
material was prepared using the method described in Example 9 for the 
preparation of 4-(pyrid-4-yl)bromobenzene but using 5-bromopyrimidine as 
starting material in place of 4-bromopyridine. There was thus obtained 
4-(pyrimidin-5-yl)bromobenzene as a solid, m.p. 138.degree.-140.degree. 
C.; NMR: 7.69-7.83(4H,m), 9.15(2H,s) and 9.21(1H,s); m/z 235(M+H). 
EXAMPLE 11 
Ar.sup.2 =3-methyl-1,2,4-oxadiazol-5-yl 
Purified by crystallisation from acetonitrile to give the title compound as 
a solid, m.p. 198.degree.-199.degree. C.; NMR: 1.2-1.4(1H,m), 
1.5-1.7(1H,m), 1.8-2.0(3H,m), 2.43(3H,s), 2.6-2.8(4H,m), 2.8-2.9(1H,d), 
3.05-3.15(1H,d), 5.72(1H,s), 7.64(2H,d) and 8.07(2H,d). 
The compound of formula 2 (Z=iodo) was prepared as follows. 
Acetamidoxime hydrochloride (1.5 g) was added portionwise to an ice-cooled 
suspension of sodium hydride (1.18 g of a 60% dispersion in oil) in dry 
tetrahydrofuran (40 ml) under an atmosphere of argon. Molecular sieve type 
4A (8-12 mesh) were added followed by a solution of ethyl 4-iodobenzoate 
(3.73 g) in tetrahydrofuran (10 ml). The mixture was heated at 65.degree. 
C. for 3 hours. The mixture was cooled to ambient temperature and 
partitioned between ethyl acetate and water. The organic extract was 
separated, washed with saturated brine, dried (MgSO.sub.4) and evaporated. 
The residue was purified by flash column chromatgraphy on silica gel using 
a 70:30 (v/v) mixture of ethyl acetate/hexane as eluent to give 
3-methyl-5-(4-iodophenyl)-1,2,4-oxadiazole as a solid (1.12 g), m.p. 
136.degree.-7.degree. C.; microanalysis, found: C, 38.2; H, 2.5; H, 9.5%; 
C.sub.9 H.sub.7 IN.sub.2 O requires: C, 37.8; H, 2.47; N, 9.79%; NMR: 
2.41(3H,s), 7.84(2H,d) and 8.02(2H,d); m/z 287(M+H). 
EXAMPLE 12 
Ar.sup.2 =5-ethyl-1,2,4-oxadiazol-3-yl 
Purified by flash column chromatography on silica gel using 10% methanol in 
dichloromethane containing 1% ammonia (density, 0.88 g/cm.sup.3) as 
eluent, followed by recrystallisation from acetonitrile to give the title 
compound as a solid, m.p. 188.degree.-189.degree. C.; NMR: 1.2-1.4(1H,m), 
1.34(3H,t), 1.5-1.7(1H,m), 1.8-2.0(3H,m), 2.6-2.8(4H,m), 2.8-2.9(1H,d), 
3.02(2H,q), 3.05-3.15(1H,d), 5.66(1H,s), 7.59(2H,d) and 8.00(2H,d). 
The compound of formula 2 (Z=iodo), 
3-(4-iodophenyl)-5-ethyl-1,2,4-oxadiazole, used as starting material was 
prepared by the method described in Example 8 for the preparation of 
3-(4-iodophenyl)-5-methyl-1,2,4-oxadiazole but using propionyl chloride in 
place of acetyl chloride. There was thus obtained 
3-(4-iodophenyl)-5-ethyl-1,2,4-oxadiazole as an oil; NMR: 1.35(3H,t), 
3.01(2H,q), 7.76(2H,d), 7.94(2H,d); m/z 301(M+H). 
EXAMPLE 13 
Ar.sup.2 =5-isopropyl-1,2,4-oxadiazol-3-yl 
Purified by crystallisation from methanol to give the title compound as a 
solid, m.p. 201.degree.-202.degree. C.; NMR: 1.35-1.90(2H,m), 1.53(6H,d), 
1.90-2.24(3H,m), 2.75-2.95(4H,m), 2.85-3.08(1H,d), 3.18-3.31(1H,d), 
3.35-3.63(1H,m), 5.80(1H,s), 7.72(2H,d) and 8.14(2H,d). 
The compound of formula 2 (Z=iodo), 
3-(4-iodophenyl)-5-isopropyl-1,2,4-oxadiazole, used as starting material 
was prepared by the method described in Example 8 for the preparation of 
3-(4-iodophenyl)-5-methyl-1,2,4-oxadiazole but using isobutyryl chloride 
in place of acetyl chloride. There was thus obtained 
3-(4-iodophenyl)-5-isopropyl-1,2,4-oxadiazole was an oil; microanalysis, 
found: C, 42.4; H, 3.5; N, 8.5%; C.sub.11 H.sub.11 IN.sub.2 O requires: C, 
42.1; H, 3.53; N, 8.92%; NMR(CDCl.sub.3): 1.45(6H,d), 3.17-3.40(1H,m) and 
7.81(4H,s); m/z 315(M+H). 
EXAMPLE 14 
Ar.sup.2 =2-benz-1,3-thiazolyl 
Solid precipitated after mixture basified with sodium hydroxide solution. 
The solid was collected by filtration, washed with dichloromethane 
followed by water and recrystallised from methoxyethanol to give the title 
compound as a solid, m.p. 248.degree.-249.degree. C.; NMR: 1.3-1.5(1H,m), 
1.6-1.8(1H,m), 1.9-2.1(3H,m), 2.7-2.9(4H,t), 2.9-3.05(1H,d), 
3.15-3.3(1H,d), 5.4(1H,m), 7.4-7.6(4H,m) and 8.0-8.2(4H,m). 
The compound of formula 2 (Z=Br) was prepared by the method of JACS., 55, 
(1971), 309. 
EXAMPLE 15 
Ar.sup.2 =2-benz-1,3-oxazolyl 
Solid precipiated after mixture basified with sodium hydroxide solution. 
The solid was collected by filtration, washed with dichloromethane 
followed by water and recrystallised from m-ethoxyethanol to give the 
title compound as a solid, m.p. 277.degree.-278.degree. C.; NMR: 
1.25-1.45(1H,m), 1.55-1.8(1H,m), 1.8-2.1(3H,m), 2.6-3.25(6H,m), 5.7(1H,s), 
7.3-7.5(2H,m), 7.55-7.7(2H,d), 7.7-7.9(2H,m) and 8.1-8.3(2H,d). 
The compound of formula 2 (Z=Br) was prepared by the method of Helv. Chim. 
Acta., 63, (1980), 418. 
EXAMPLE 16 
Ar.sup.2 =1-methyl-indol-2-yl 
Solid precipitated after mixture basified with sodium hydroxide solution. 
The solid was collected by filtration, washed with dichloromethane 
followed by water and recrystallised from methoxyethanol to give the title 
compound as a solid, m.p. 238.degree.-239.degree. C.; NMR: 1.3-1.5(1H,m), 
1.6-1.8(1H,m), 1.85-2.15(3H,m), 2.6-3.6(6H,m), 3.75 (3H,s), 5.7(1H,s), 
6.6(1H,s), 7.0-7.4(2H, m) and 7.4-7.7(4H,m). 
The compound of formula 2 was prepared as follows. 
Potassium tert-butoxide (1.23 g) was added to a solution of 
2-(4-bromophenyl)indole (2.72 g) in dimethylformamide (40 ml). Iodomethane 
(1.25 ml) was added and the reaction mixture stirred at ambient 
temperature for 18 hours. The reaction mixture was added to water. This 
solid was collected by filtration and purified by vacuum chromatography on 
silica gel (Merck Art. 7736) using 5% ethyl acetate/hexane as eluent to 
give 2-(4-bromophenyl)-1-methylindole (1.625 g) as a solid, m.p. 
114.degree.-115.degree. C. 
EXAMPLE 17 
Ar.sup.2 =2-quinolyl 
Solid precipiated after mixture basified with sodium hydroxide solution. 
The solid was collected by filtration, washed with dichloromethane 
followed by water and recrystallised from methoxyethanol to give the title 
compound as a solid, m.p. 246.degree.-248.degree. C.; NMR: 1.2-1.4(1H,m), 
1.5-1.8(1H,m), 1.8-2.1(3H,m), 2.6-3.15(5H,m), 3.2-3.3(1H,d), 5.7(1H,s), 
7.5-7.7(3H,m), 7.7-7.9(1H,t), 7.9-8.1(2H,m), 8.1-8.2(1H,d), 8.2-8.4(2H,d) 
and 8.4-8.5(1H,d). 
The compound of formula 2, 2-(4-bromophenyl)quinoline, used as starting 
material was prepared using the method of Suzuki et al, Sn. Comm., 11, 
(1981), 513 as a solid, m.p. 115.degree. C. 
EXAMPLE 18 
Ar.sup.2 =2-indolyl 
Solid precipiated after mixture basified with sodium hydroxide solution. 
The solid was collected by filtration, washed with dichloromethane 
followed by water and recrystallised from aqueous dimethylformamide to 
give the title compound as a solid, m.p. 267.degree.-272.degree. C.; NMR: 
1.2-1.45(1H,m), 1.5-1.8(1H,m), 1.8-2.1(3H,m), 2.6-3.5(6H,m), 5.6(1H,s), 
6.9-7.2(3H,m), 7.3-7.6(4H,m) and 7.7-7.9(2H,d). 
The compound of formula 2, 2-(4-bromophenyl)indole, used as starting 
material was prepared from 4-bromoacetophenone using the method described 
in J. Med. Chem., 7, (1964), 737 as a solid, m.p. 210.degree.-212.degree. 
C. 
EXAMPLE 19 
Ar.sup.2 =5-methoxy-1-methyl-pyrazol-3-yl 
Extracted with ethyl acetate in place of dichoromethane. Crystallised from 
acetonitrile to give the title compound as a solid, m.p. 
194.degree.-196.degree. C.; NMR: 1.2-1.4(1H,m), 1.5-1.7(1H,m), 
1.8-2.0(3H,m), 2.6-2.8(4H,t), 2.8-2.9(1H,d), 3.0-3.1(1H,d), 3.6(3H,s), 
3.9(3H,s), 5.6(1H,s), 6.2(1H,s), 7.4-7.5(2H,d) and 7.7-7.8(2H,d). 
The compound of formula 2, 3-(4-bromophenyl)-5-methoxy-1-methylpyrazole, 
used as starting material was prepared as follows. 
A mixture of 3-(4-bromophenyl)-5-hydroxy-1-methylpyrazole (2.5 g), acetone 
(200 ml), potassium carbonate (1.6 g) and methyl iodide (1.4 g) was heated 
at reflux for 2 hours. The mixture was filtered and the filtrate was 
evaporated. The residue was purified by flash column chromatography on 
silica gel using 10% ethyl acetate/toluene as eluent to give 
3-(4-bromophenyl)-5-methoxy-1-methypyrazole (590 mg) as a solid, m.p. 
71.degree.-73.degree. C.; NMR: 3.6(3H,s), 3.9(3H,s), 6.2(1H,s), 
7.5-7.6(2H,d) and 7.6-7.7(2H,d). 
The 3-(4-bromophenyl)-5-hydroxy)-5-hydroxy-1-methylpyrazole was prepared 
using the method of Veibel et al., Acta. Chem. Scand., 8, (1954) 774 but 
using ethyl 4-bromobenzoyl acetate as starting material. There was thus 
obtained 3-(4-bromophenyl)-5-hydroxy-1-methylpyrazole (73% yield) as a 
solid, m.p. 196.degree.-199.degree. C.; NMR: 3.6(3H,s), 5.8(1H,s) and 
7.5-7.7(4H,dd). 
EXAMPLE 20 
Ar.sup.2 =5-isoxazolyl 
Purified by flash column chromagraphy on silica gel using 10% methanol in 
dichloromethane containing 1% ammonia (density, 0.88 g/cm.sup.3) as 
eluent, followed by recrystallisation from acetonitrile to give the title 
compound as a solid, m,p. 175.degree.-178.degree. C.; NMR: 1.2-1.4(1H,m), 
1.5-1.7(1H,m), 1.8-2.0(3H,m), 2.6-2.8(4H,m), 2.8-2.9(1H,d), 
3.03-3.15(1H,d), 5.68(1H,s), 7.06(1H,d), 7.55(2H,d), 7.86(2H,d) and 
8.65(1H,d). 
The compound of formula 2 used as starting material was prepared as 
follows. 
A solution of 4-iodoacetophenone (6.15 g) in N,N-dimethylformamide dimethyl 
acetal (6.5 ml) was heated at reflux for 8 hours. The reaction mixture was 
evaporated and the solid residue was recrystallised from acetonitrile to 
give 1-(4-iodophenyl)-3-dimethylamino-2-propen-1-one (4.38 g), as a solid, 
m.p. 117.degree.-118.degree. C.; NMR(CDCl.sub.3): 2.60-3.50(6H,br.d), 
5.64(1H,d), 7.62(2H,d), 7.77(2H,d) and 7.80(1H,d), m/z 302(M+H). A mixture 
of 1-(4-iodophenyl)-3-dimethylamino-2-propen-1-one (3.0 g) and 
hydroxylamine hydrochloride (0.73 g) in 1:1 dioxane/water (30 ml) was 
stirred at ambient temperature for 48 hours. Addition of water gave a 
solid which was collected by filtration, washed with water, and purified 
by flash column chromagatography on silica gel using 1:1 (v/v) ethyl 
acetate/pentane as eluent. There was thus obtained 
5-(4-iodophenyl)-isoxazole (0.6 g); microanalysis found: C, 39.4; H, 2.3; 
N, 4.8%; C.sub.9 H.sub.6 INO requires: C, 39.9; H, 2.23; N, 5.17%; 
NMR(CDCl.sub.3): 6.54(1H,d), 7.52(2H,d), 7.83(2H,d) and 8.28(1H,d); m/e 
272(M+H). 
EXAMPLE 21 
Ar.sup.2 =5-methyl-1,3-oxazol-2-yl 
Purified by flash column chromatography on silica gel using a mixture of 
15% methanol in dichloromethane containing 1% ammonia (density, 0.88 
g/cm.sup.3) as eluent, followed by recrystallisation from acetonitrile to 
give the title compound as a solid, m.p. 175.degree.-176.degree. C.; NMR: 
1.2-1.4(1H,m), 1.5-1.7(1H,m), 1.8-2.0(3H,m), 2.38(3H,s), 2.6-2.8(4H,m), 
2.8-2.9(1H,d), 3.05-3.15(1H,d), 5.64(1H,s), 7.01(1H,d), 7.52(2H,d) and 
7.90(2H,d). 
The compound of formula 2 used as starting material was prepared as 
follows. 
A solution of propargylamine (3.55 g) in ethyl acetate (25 ml) was added 
over a period of 15 minutes to a stirred mixture of 4-bromobenzoyl 
chloride (14.2 g) and sodium carbonate (10.6 g) in ethyl acetate (100 ml) 
at ambient temperature. The mixture was heated at reflux for 1 hour. The 
mixture was cooled to ambient temperature and water (200 ml) was added. 
The mixture extracted with ethyl acetate (2.times.100 ml). The ethyl 
acetate extracts were combined, washed with saturated aqueous sodium 
bicarbonate solution, saturated with brine, dried (MgSO.sub.4) and 
evaporated. The solid residue was recrystallised from ethyl acetate to 
give 4-bromobenzoyl propargyl amide (8.9 g), m.p. 281.degree.-288.degree. 
C.; NMR: 3.10(1H,m), 4.05(2H,m), 7.69(2H,m), 7.80(2H,m), 9.0(1H,m); m/z 
238(M+H). 
Mercuric acetate (40 mg) was added to a stirred suspension of 
4-bromobenzoyl propargyl amide (3.57 g) in acetic acid (30 ml) and the 
mixture heated at reflux for 1.25 hours. The mixture was cooled to ambient 
temperature, evaporated and the residue azeotroped with toluene to give a 
solid which was purified by column chromatography on silica gel (Merck 
7734) using 30% ethyl acetate/hexane as eluent. There was thus obtained 
2-(4-bromophenyl)-5-methyloxazole (2.75 g), m.p. 66.degree.-68.degree. C.; 
NMR(CDCl.sub.3): 2.40(3H,s); 6.81(1H,d), 7.52(2H,m) and 7.82(2H,m); m/z 
238(M+H). 
EXAMPLE 22 
Ar.sup.2 =5-ethoxycarbonyl-1,2,4-oxadiazol-3-yl 
Purified by crystallisation from acetonitrile to give the title compound as 
a solid, m.p. 153.degree.-154.degree. C.; NMR: 1.2-1.4(1H,m), 1.37(3H,t), 
1.5-1.7(1H,m), 1.75-2.05(3H,m), 2.55-3.20(6H,br m), 4.47(2H,q), 
5.68(1H,s), 7.6(2H, d of d) and 8.03(2H, d of d). 
The compound of formula 2 (Z=iodo), 
5-ethoxycarbonyl-3-(4-iodophenyl)-1,2,4-oxadiazole, used as starting 
material, was prepared by the method described in Example 8 for the 
preparation of 3-(4-iodophenyl)-5-methyl-1,2,4-oxadiazole but using ethyl 
oxalyl chloride in place of acetyl chloride. There was thus obtained 
5-ethoxycarbonyl-3-(4-iodophenyl)-1,2,4-oxadiazole as a solid, which was 
recrystallised from acetonitrile, m.p. 107.degree.-108.degree. C.; 
microanalysis found: C, 38.3; H, 2.6; N, 7.9%; C.sub.11 H.sub.9 IN.sub.2 
O.sub.3 requires: C, 38.4; H, 2.64; N, 8.14%; NMR(CDCl.sub.3): 1.50(3H,t), 
4.58(2H,q) and 7.89(4H,s); m/z 345(M+H). 
EXAMPLE 23 
Ar.sup.2 =5-methyl-1,3,4-oxadizol-2-yl 
Purified by flash column chromatography on silica gel using 15% methanol in 
dichloromethane containing 1% ammonia (density, 0.88 g/cm.sup.3) as 
eluent, followed by recrystallisation from acetonitrile, to the title 
compound as a solid, m.p. 217.degree.-218.degree. C.; NMR: 1.2-1.4(1H,m), 
1.5-1.7(1H,m), 1.8-2.0(3H,m), 2.58(3H,s), 2.6-2.8(4H,m), 2.8-2.9(1H,d), 
3.05-3.15(1H,d), 5.67(1H,s), 7.60(2H,d) and 7.95(2H,d). 
The compound of formula 2 2-(4-bromophenyl)-5-methyl-1,3,4-oxadiazole, used 
as starting material was prepared using the method described in Example 32 
for the preparation of 2-(4-bromophenyl)-5-ethyl-1,3,4-oxadiazole but 
using triethylorthoacetate in place of triethylorthopropionate. There was 
thus obtained 2-(4-bromophenyl)-5-methyl-1,3,4-oxadiazole as a solid m.p. 
116.degree.-117.degree. C.; microanalysis found: C, 45.1; H, 2.8; N, 
11.6%; C.sub.9 H.sub.7 BrN.sub.2 O requires: C, 45.2; H, 2.95; N, 11.7%; 
NMR(CDCl.sub.3): 2.63(3H,s), 7.65(2H,d) and 7.90(2H,d); m/z 239(M+H). 
EXAMPLE 24 
Ar.sup.2 =5-methoxy-3-methylpyrazol-1-yl 
Aqueous sodium hydroxide solution (10 ml) was added to the reaction mixture 
and the mixture extracted with diethyl ether. The organic extracts were 
dried (MgSO.sub.4) and evaporated to give a solid residue which was 
recrystallised from acetonitrile to give the title compound as a solid, 
m.p. 152.degree.-154.degree. C.; NMR: 1.2-1.4(1H,m), 1.5-1.7(1H,m), 
1.8-2.0(3H,m), 2.15(3H,s), 2.6-2.75(4H,t), 2.75-2.9(1H,d), 3.0-3.15(1H,d), 
3.9(3H,s), 5.6(1H,s), 6.7(1H,s), 7.4-7.5(2H,d) and 7.6-7.7(2H,d). 
The compound of formula 2, 1-(4-bromophenyl)-5-methoxy-3-methylpyrazole, 
used as starting material was prepared as follows. 
A mixture of 1-(4-bromophenyl)-3-methyl-pyrazol-5-one (3.6 g), 10N aqueous 
sodium hydroxide solution (1.57 ml), methanol (5 ml) and dimethylsulphate 
(1.4 ml) was heated at reflux for 2 hours. The crude product was purified 
by vacuum flash chromatography on silica gel (Merck Art 7736) using 
dichloromethane as eluent to give 
1-(4-bromophenyl)-5-methoxy-3-methylpyrazole (21% yield) as a solid, m.p. 
67.degree.-68.degree. C.; NMR: 2.9(3H,s), 3.4(3H,s), 5.5(1H,s) and 
7.4-7.5(2H,d). 
EXAMPLE 25 
Ar.sup.2 =2-methyl-5-hydroxypyrid-6-yl 
Purified by flash column chromatography on silica gel using 10% methanol in 
dichloromethane containing 1% ammonia (density, 0.88 g/cm.sup.3) as eluent 
to give the title compound as a solid, m.p. 253.degree.-256.degree. C.; 
NMR: 1.25-1.45(1H,m), 1.55-1.75(1H,m), 1.8-2.03(3H,m), 2.4(3H,s), 
2.65-2.8(4H,m), 2.85-2.92(1H,d), 3.08-3.15(1H,d), 5.67(1H,br), 
7.03-7.08(1H,d), 7.2-7.25(1H,d), 7.4-7.48(2H,d), 8.02-8.1(2H,d) and 
9.97(1H,br). 
The compound of formula 2 used as starting material was prepared as 
follows. 
A solution of 4-bromobenzeneboronic acid (2.0 g) in ethanol (10 ml) was 
added over a period of 15 minutes to a stirred mixture of 
6-iodo-2-picolin-5-ol (2.35 g), saturated aqueous sodium carbonate 
solution (5.0 ml), tetrakis(triphenylphosphine)palladium 0! (280 mg) and 
toluene (10 ml) under an atmosphere of argon. The mixture was stirred at 
reflux for 6 hours. The mixture was evaporated and the residue was treated 
with water (20 ml). The mixture was filtered and the yellow solid 
collected was purified by flash column chromatography on alumina (1CN 
Biomedicals Alumina N32-63) using 50% n-pentane/ethyl. acetate as eluent 
to give 2-(4-bromophenyl)-3-hydroxy-6-methylpyridine (600 mg), m.p. 
196.degree.-199.degree. C.; NMR: 2.42(3H,s), 7.09(1H,d), 7.25(1H,d), 
7.62(2H,d), 8.02(2H,d), 9.98(1H,s); m/z 264 & 266 (M+H). 
EXAMPLE 26 
Ar.sup.2 =2-methoxypyrid-5-yl 
Purified by flash column chromatography on silica gel using 10% methanol in 
ethyl acetate containing 1% ammonia (density, 0.88 g/cm.sup.3) as eluent, 
followed by recrystallisation from acetonitrile, to give the title 
compound as a solid, m.p. 193.degree.-195.degree. C.; NMR: 1.2-1.45(1H,m), 
1.55-1.75(1H,m), 1.85-2.03(3H,m), 2.65-2.8(4H,m), 2.85-2.92(1H,d), 
3.08-3.15(1H,d), 3.9(3H,s), 5.67(1H,br), 6.89-6.95(1H,d), 7.45-7.53(2H,d), 
7.63-7.71(2H,d), 8.0-8.08(1H, d of d) and 8.5(1H,d). 
The compound of formula 2 was prepared as follows. 
Sodium hydride (2.0 g of a 60% dispersion in mineral oil) was added 
portionwise to methanol (30 ml) with stirring and cooling with an 
ice-bath. 2,5-Dibromopyridine (2.37 g) was added to the mixture and the 
mixture stirred at reflux for 16 hours. The methanol was removed by 
evaporation. Water (15 ml) was added to the residue and the mixture was 
extracted with dichloromethane (3.times.15 ml). The organic extracts were 
combined, dried (MgSO.sub.4) and evaporated to give 
5-bromo-2-methoxypyridine (2.0 g) as an oil, NMR: 3.85(3H,s), 6.83(1H,d), 
7.9(1H,dd) and 8.3(1H,d). 
The 5-bromo-2-methoxypyridine was reacted with 4-bromobenzeneboronic acid 
using the procedure described in Example 25 for the preparation of the 
compound of formula 2. The product was purified by flash column 
chromatography on silica gel using a gradient of n-pentane to 3% ethyl 
acetate in n-pentane to give 5-(4-bromophenyl)-2-methoxypyridine as an oil 
(0.56 g), NMR: 3.9(3H,s), 6.9(1H,d), 7.61(4H,s), 8.0(1H,dd) and 8.5(1H,d). 
EXAMPLE 27 
Ar.sup.2 =3-ethoxycarbonylpyrid-5-yl 
Purified by flash column chromatography on silica gel using 10% methanol in 
dichloromethane containing 1% ammonia (density, 0.88 g/cm.sup.3) as eluent 
to give the title compound as a solid, m.p. 162.degree.-165.degree. C.; 
NMR: 1.39(3H,t), 1.6-1.8(1H,m), 1.8-2.0(1H,m), 2.08-2.3(3H,m), 
3.02-3.2(4H,m), 3.22(1H,d), 3.5(1H,d), 4.41(2H,q), 5.67(1H,br), 
7.5-7.6(2H,d), 7.8-7.9(2H,d), 8.48(1H,t) and 9.09(2H,d). 
The compound of formula 2 was prepared using the method described in 
Example 25 for the preparation of the compound of formula 2 but using 
ethyl-5-bromonicotinate (1.15 g) in place of 6-iodo-2-picolin-5-ol. There 
was thus obtained, after trituration with n-pentane, 
ethyl-5-(4-bromophenyl)nicotrinate (1.0 g) as a solid, m.p. 
72.degree.-76.degree. C.; NMR: 1.37(3H,t), 4.4(2H,q), 7.75(4H,m), 
8.45(1H,t), 9.1(2H,d); m/z 306 and 308(M+H). 
EXAMPLE 28 
Ar.sup.2 =2-ethylpyrid-5-yl 
Purified by flash column chromatography on silica gel using a gradient of 
5% methanol in dichloromethane containing 1% ammonia (density, 0.88 
g/cm.sup.3) to 10% methanol in dichloromethane containing 1% ammonia 
(density, 0.88 g/cm.sup.3) as eluent to give the title compound as a 
solid, m.p. 203.degree.-206.degree. C.; NMR: 1.2-1.3(3H,t), 
1.2-1.45(1H,m), 1.55-1.75(1H,m), 1.85-2.03(3H,m), 2.65-2.8(4H,m), 
2.75-2.85(2H,q), 2.85-2.92(1H,d), 3.08-3.15(1H,d), 5.67(1H,br), 
7.31-7.4(1H,d), 7.48-7.56(2H,d), 7.68-7.76(2H,d), 7.97-8.04(1H, d of d) 
and 8.8(1H,d). 
The compound of formula 2 was prepared using the method described in 
Example 25 for the preparation of the compound of formula 2 but using 
5-bromo-2-ethylpyridine (1.86 g) in place of 6-iodo-2-picolin-5-ol. There 
was thus obtained 5-(4-bromophenyl)-2-ethylpyridine which was purified by 
flash column chromatography on silica gel using a gradient of 2% to 10% 
ethyl acetate in n-pentane as eluent to give an oil (1.2 g), NMR: 
1.3(3H,t), 2.8(2H,q), 7.35(1H,d), 7.68(4H,s), 8.0(1H,d) and 8.8(1H,d), m/z 
262 and 264 (M+H). 
The 5-bromo-2-ethyl pyridine was prepared by the method of Tilley, J. W. et 
al, JOC, 53, (1988), 386-390. 
EXAMPLE 29 
Ar.sup.2 =1,2,4-oxadiazol-3-yl 
Purified by flash column chromatography on silica gel using 10% methanol in 
dichloromethane containing 1% ammonia (density, 0.88 g/cm.sup.3) as 
eluent, followed by recrysallisation from acetonitrile to give the title 
compound as a solid, m.p. 206.degree.-207.degree. C.; NMR: 
1.21-1.45(1H,m), 1.48-1.70(1H,m), 1.75-2.03(3H,m), 2.56-2.8(4H,m), 
2.80-2.92(1H,d), 3.08-3.15(1H,d), 5.67(1H,s), 7.61(2H,d), 8.04(2H,d) and 
9,72(1H,s). 
The compound of formula 2 (Z=iodo) used as starting material was prepared 
as follows. 
A mixture of 4-iodobenzamidoxime (3.93 g) in triethylorthoformate (15 ml) 
was heated at reflux for 4 hours. The mixture was evaporated and the 
residue was purified by flash column chromatography on silica gel using 
4:1 (v/v) n-pentane/ethyl acetate as eluent to give 
3-(4-iodophenyl)-1,2,4-oxadiazole (0.74 g) as a solid; NMR(CDCl.sub.3): 
7.85(4H,s) and 8.74(1H,s); m/z 272(M). 
EXAMPLE 30 
Ar.sup.2 =2-thiazolyl 
Purified by flash column chromatography using a 4:1(v/v) mixture of 
dichloromethane/methanol as eluent to give a solid, m.p. 
210.degree.-212.degree. C.; NMR: 1.2-1.4(1H,m), 1.5-1.7(1H,m), 
1.8-2.0(3H,m), 2.6-2.8(4H,m), 2.8-2.9(1H,d), 3.05-3.15(1H,d), 5.65(1H,s), 
7.8(1H,d) and 7.93(1H,d). 
The compound of formula 2, 4-bromophenyl-2-thiazole was prepared as 
described by Erlenmeyer, H., Helv. Chim. Acta., 33, (1950), 1271. 
EXAMPLE 31 
Ar.sup.2 =3-methyl-1,2,4-thiadiazol-5-yl 
Purified by flash column chromatography using a 85:10:5 (v/v/v) mixture of 
ethyl acetate/methanol/ammonia to give the title compound as a solid, m.p. 
186.degree.-188.degree. C.; NMR: 1.2-1.4(1H,m), 1.5-1.7(1H,m), 
1.8-2.0(3H,m), 2.6-2.8(4H,m), 2.7-2.75(3H,s), 2.8-2.9(1H,d), 
3.05-3.15(1H,d) and 5.65(1H,s). 
The compound of formula 2, 3-methyl-5-(4-bromophenyl)-1,2,4-thiadiazole, 
used as starting material was prepared by the method described in J. Med. 
Chem., 33, (1990), 2052-2059. 
EXAMPLE 32 
2-ethyl-1,3,4-oxadiozol-5-yl 
Purified by flash column chromatography on silica gel using 20% methanol in 
dichloromethane containing 1% ammonia (density, 0.88 g/cm.sup.3) as 
eluent, followed by recrystallisation from acetonitrile, to give the title 
compound as a solid, m.p. 198.degree.-199.degree. C.; NMR: 
1.25-1.45(1H,m), 1.33(3H,t), 1.50-1.70(1H,m), 1.78-2.03(3H,m), 
2.65-2.8(4H,m), 2.85-2.92(1H,d), 2.94(2H,q), 3.03-3.15(1H,d), 5.65(1H,s), 
7.60(2H,d) and 7.96(2H,d). 
The compound of formula 2 was prepared as follows. 
A mixture of 4-bromobenzoic acid hydrazide (3.23 g) and 
triethylorthopropionate (25 ml) was heated at reflux for 7 hours. The 
mixture was evaporated to give a solid which was recrystallised from ethyl 
acetate to give 2-(4-bromphenyl)-5-ethyl-1,3,4-oxadiazole (3.65 g), as a 
solid, m.p. 101.degree.-102.degree. C.; microanalysis found: C, 47.3; H, 
3.6; N, 10.9%; C.sub.10 H.sub.9 BrN.sub.2 O requires: C, 47.5; H, 3.58; N, 
11.1%; NMR(CDCl.sub.3): 1.44(3H,t), 2.96(2H,q), 7.65(2H,d) and 7.90(2h,D); 
m/z 253(M+H). 
EXAMPLE 33 
Using the procedure described in Example 1, but with 
3-(4-iodophenyl)-5-methyl-1,2,4-oxadiazole in place of 
3-(4-bromophenyl)pyridine and (+)-3-ethynyl-3-hydroxyquinuclidine in place 
of 3-ethynyl-3-hydroxyquinuclidine, there was thus obtained, after 
recrystallisation from ethanol, 
(+)-3-2-(4-5-methyl-1,2,4-oxadiazol-3-yl!phenyl)ethynyl!-3-hydroxy 
quinuclidine as a solid, m.p. 210.degree.-211.degree. C.; NMR: 
1.25-1.45(1H,m), 1.55-1.75(1H,m), 1.85-2.03(3H,m), 2.65-2.8(4H,m), 
2.7(3H,s), 2.85-2.92(1H,d), 3.08-3.15(1H,d), 5.65(1H,s), 7.55-7.65(2H,d) 
and 7.93-8.03(2H,d); .alpha.!.sub.D.sup.20 =+29.0.degree. (c=1.0, 
methanol); m/z 310(M+H). 
The (+)-ethynyl-3-hydroxyquinuclidine was prepared as follows. 
A solution of (.+-.)-3-ethynyl-3-butyryloxyquinuclidine (4.42 g) in 
deionised water (700 ml) containing methanol (35 ml) was adjusted to pH 
7.0 using an 0.1M aqueous sodium hydroxide solution (dispensed by a pH 
autotitrater). A suspension of pig liver eaterase (8.0 ml, 9200 units, in 
3.2M aqueous ammonium sulphate solution at pH8; Sigma Chemical Company 
Ltd) was added to the reaction mixture and the mixture was stirred at 
ambient temperature whilst maintaining the pH at 7.0 using 0.1M aqueous 
sodium hydroxide solution (dispensed by a pH autotitrater). After 5.5 
hours, 7.3 ml of the sodium hydroxide solution had been consumed, 
indicating that the hydrolysis was 35% complete. The pH of the reaction 
mixture was adjusted to 2.5 using 2M aqueous hydrochloric acid and the 
mixture was stirred for 10 minutes. 2M aqueous sodium hydroxide solution 
was then added to the mixture to give a pH of 7.05 and the mixture 
extracted with diethyl ether (3.times.200 ml, followed by 12.times.150 
ml). The aqueous phase was separated, and freeze dried over a period of 48 
hours to give a solid which was dissolved in deionised water (30 ml). The 
solution was filtered and the filtrate was basified to pH9 using 10.8M 
sodium hydroxide solution to give a solid. The solid was collected by 
filtration to give (+)-3-ethynyl-3-hydroxyquinuclidine, (554 mg) m.p. 
204.degree.-207.degree. C., .alpha.!.sup.20.sub.D =54.5.degree. (C=0.99, 
methanol). 
The (.+-.)-3-ethynyl-3-butyryloxyquinuclidine used as starting material was 
prepared as follows. 
A solution of n-butyl lithium (100 ml of a 2M solution in pentane) was 
added portion-wise over a period of 20 minutes to a stirred solution of 
ethynyltrimethylsilane (19.6 g) in dry tetrahydrofuran (400 ml) at 
-70.degree. C. The mixture was stirred for 1 hour at -70.degree. C. A 
solution of 3-quinuclidinone (2.4 g) in dry tetrahydrofuran (100 ml) was 
then added and the mixture stirred for 1 hour at -70.degree. C. Methanol 
(1 ml) was then added to the mixture and the mixture allowed to warm to 
ambient temperature. The solvents were removed by evaporation. Methanol 
(500 ml) and potassium carbonate (40 g) were added to the residue and the 
mixture was stirred for 1 hour. The solvent was removed by evaporation. 
The residue was triturated with water (500 ml) and then dried in vacuo to 
give 3-ethynyl-3-hydroxy-quinuclidine as a solid, m.p. 
193.degree.-197.degree. C.; NMR(DMSO-d.sub.6): 1.5-1.3(1H,m), 
1.4-1.6(1H,m), 1.7-1.95(3H,m), 2.55-2.8(5H,m), 2.95(1H,d), 3.3(1H,d) and 
5.4(1H,s); m/z 152 (M+H). 
A mixture of (.+-.)-3-ethynyl-3-hydroxyquinuclidine (15.1 g) and butyric 
anhydride (60 ml) was stirred at 120.degree. C. for 5 hours. The reaction 
mixture was cooled to ambient temperature, added to a saturated aqueous 
solution of sodium carbonate (1 l) and stirred for 3 hours. The mixture 
was extracted with diethyl ether (3.times.100 ml). The diethyl ether 
extracts were combined, washed with saturated aqueous sodium carbonate 
solution, dried (MgSO.sub.4) and evaporated to give 
(.+-.)-3-ethynyl-3-butyryloxyquinuclidine as an oil, NMR(200 MHz, 
DMSOd.sub.6): 0.90(3H,t), 1.40(1H,m), 1.57(4H,m), 1.85(1H,m), 2.28(3H,m), 
2.66(4H,m), 3.03(1H,d), 3.18(1H,d) and 3.55(1H,s). 
EXAMPLE 34 
The procedure described in Example 33 was repeated using 
(-)-3-ethynyl-3-hydroxyquinuclidine in place of 
(+)-3-ethynyl-3-hydroxyquinuclidine to give 
(-)-3-2-(4-5-methyl-1,2,4-oxadiazol-3-yl!phenyl)ethynyl!-3-hydroxy 
quinuclidine as a solid, m.p. 211.degree.-212.degree. C.; NMR: 
1.25-1.45(1H,m), 1.55-1.75(1H,m), 1.85-2.03(3H,m), 2.65-2.8(4H,m), 
2.7(3H,s), 2.85-2.92(1H,d), 3.08-3.15(1H,d), 5.65(1H,s), 7.5-7.7(2H,d) and 
7.93-8.03(2H,d); .alpha.!.sub.D.sup.20 =-31.2.degree. (c=1, methanol); 
m/z 310(M+H). 
The (-)-3-ethynyl-3-hydroxyquinuclidine was prepared as follows. 
A solution of (.+-.)-3-ethynyl-3-butyryloxy quinuclidine (4.42 g) in 
deionised water (700 ml) containing methanol (35 ml) was adjusted to pH 
7.0 using 0.1M aqueous sodium hydroxide solution (dispensed by a pH 
autotitrator). A suspension of pig liver esterase (3.0 ml, 3450 units, in 
3.2M aqueous ammonium sulphate solution at pH8; Sigma Chemical Company 
Ltd) was added to the reaction mixture and the mixture stirred at ambient 
temperature for 46 hours whilst maintaining the pH at 7.0 using 0.1M 
aqueous sodium hyroxide solution (dispensed from a pH autotitrater). 
During this period 112.5 ml of the sodium hydroxide solution was consumed, 
indicating that the hydrolysis was 56% complete. The pH of the reaction 
mixture was adjusted to 2.52 using 2M aqueous hydrochloric acid and the 
mixture stirred for 20 minutes. 2M aqueous sodium hydroxide solution was 
added to the mixture to give a pH of 7.01 and the mixture extracted with 
diethyl ether (12.times.150 ml). The diethyl ether extracts were combined, 
dried (MgSO.sub.4) and evaporated to give an oil (2.43 g) containing 
(-)-3-ethynyl-3-butyryloxyquinuclidine and some butyric acid. 
The above oil containing (-)-3-ethynyl-3-butyryloxyquinuclidine was treated 
with a solution of potassium hydroxide (2.24 g) in methanol (50 ml). The 
mixture was stirred at ambient temperature for 2 hours. The mixture was 
evaporated and deionised water (2 ml) was added to the residue to give a 
solid. The solid was collected by filtration, washed with water (2.times.2 
ml) and dried under vacuum over phosporus pentoxide to give 
(-)-3-ethynyl-3-hydroxyquinuclidine (611 mg) as a solid, m.p. 
199.degree.-202.degree. C., .alpha.!.sup.19.sub.D =-56.1.degree. (C=1.02, 
methanol). 
EXAMPLE 35 
Using a procedure similar to that described in Example 1, but using 
3-(3-bromophenyl)-5-methyl-1,2,4-oxadiazole in place of 
3-(4-bromophenyl)pyridine, there was obtained (after purification by flash 
column chromatography on silica gel using 10% methanol in dichloromethane 
containing 1% ammonia, as eluent, followed by recrystallisation from 
acetonitrile) 
3-2-(3-5-methyl-1,2,4-oxadiazol-3-yl!phenyl)ethynyl!-3-hydroxyquinuclidi 
ne as a solid, m.p. 182.degree.-183.degree. C.; NMR: 1.25-1.45(1H,m), 
1.50-1.75(1H,m), 1.78-2.03(3H,m), 2.55-2.8(4H,m), 2.67(3H,s), 
2.78-2.92(1H,d), 3.05-3.15(1H,d), 5.65(1H,s), 7.50-7.65(2H,m) and 
7.9-8.01(2H,m). 
The compound of formula 2, 3-(3-bromophenyl)-5-methyl-1,2,4-oxadiazole was 
prepared from 3-bromobenzonitrile using the method described in Example 8 
for the preparation of 3-(4-iodophenyl)-5-methyl-1,2,4-oxadiazole. There 
was thus obtained 3-(3-bromophenyl)-5-methyl-1,2,4-oxadiazole as a solid, 
m.p. 78.degree.-79.degree. C.; microanalysis, found: C, 44.9; H, 2.8; N, 
11.5%; C.sub.9 H.sub.7 BrN.sub.2 O requires: C, 45.2; H, 2.95; N, 11.7%; 
NNR: 2.67(3H,s), 7.51-7.58(1H,m), 7.80(1H,dd), 8.00(1H,dd) and 8.11(1H,d); 
m/z 239 (M+H). 
EXAMPLE 36 
Using a procedure similar to that described in Example 1, but using 
3-methyl-5-(3-bromophenyl)-1,2,4-oxadiazole in place of 
3-(4-bromophenyl)pyridine, there was obtained after purification by flash 
column chromatography on silica gel using 10% methanol in dichloromethane 
containing 1% ammonia (density, 0.88 g/cm.sup.3) as eluent! 
3-2-(3-3-methyl-1,2,4-oxadiazol-5-yl!phenyl)ethnynyl!-3-hydroxy 
quinuclidine as a solid, m.p. 178.degree.-180.degree. C.; NMR: 
1.25-1.45(1H,m), 1.52-1.73(1H,m), 1.80-2.06(3H,m), 2.45(3H,s), 
2.65-2.8(4H,m), 2.82-2.95(1H,d), 3.08-3.22(1H,d), 5.70(1H,s), 
7.60-7.78(2H,m) and 8.04-8.13(2H,m). 
The starting material, 3-methyl-5-(3-bromophenyl)-1,2,4-oxadiazole, was 
prepared from ethyl-3-bromobenzoate using the method described in Example 
11 for the preparation of 3-methyl-5-(4-iodophenyl)-1,2,4-oxadiazole. 
There was thus obtained 3-methyl-5-(3-bromophenyl)-1,2,4-oxadiazole as a 
solid, m.p. 90.degree.-92.degree. C.; microanalysis, found: C, 45.4; H, 
2.9; N, 11.3%; C.sub.9 H.sub.7 BrN.sub.2 O requires: C, 45.2; H, 2.95; N, 
11.7%; NMR: 2.43(3H,s), 7.59(1H,t), 7.91(1H,dd), 8.10(1H,dd), 8.20(1H,d); 
m/z 239 (M+H). 
EXAMPLE 37 
The procedure described in Example 1 was repeated but using 
3-methyl-5-(3-allyl-4-trifluoromethylsulphonyloxyphenyl-1,2,4-oxadiazole 
in place of 3-(4-bromophenyl)pyridine. There was thus obtained, after 
recrystallisation from acetonitrile, 
3-2-(2-allyl-4-(3-methyl-1,2,4-oxazdiazol-5-yl)phenylethynyl!-3-hydroxyqu 
inuclidine as a solid, m.p. 164.degree.-165.degree. C.; NMR: 
1.25-1.45(1H,m), 1.52-1.72(1H,m), 1.8-2.05(3H,m), 2.41(3H,s), 
2.67-2.8(4H,m), 2.8-2.45(1H,d), 3.1-3.25(1H,d), 3.61(2H,d), 
5.06-5.20(2H,d), 5.70(1H,s), 5.42-6.10(1H,m), 7.61(1H,d) and 
7.89-8.00(2H,m). 
The 
3-methyl-5-(3-allyl-4-trifluoromethylsulphonyloxyphenyl)-1,2,4-oxadiazole 
was prepared by treating 
3-methyl-5-(3-allyl-4-hydroxyphenyl)-1,2,4-oxadiazole with triflic 
anhydride in pyridine at 0.degree. C. using the procedure described in 
Example 43 to give an oil which was used without further purification. 
EXAMPLE 38 
A solution of hydrogen chloride in ethanol was added dropwise to a stirred 
solution of 
3-2-allyl-4-(3-methyl-1,2,4-oxadiazol-5-yl)phenoxymethyl!-3-hydroxyquinuc 
lidine borane complex (0.7 g) in acetone (7 ml) until the solution was pH1. 
The solution was stirred at ambient temperature for 1 hour. The mixture 
was diluted with ether (5 ml) and stirred for 30 minutes. The solid was 
collected by filtration and washed with ether to give 
3-2-allyl-4-(3-methyl-1,2,4-oxadiazol-5-yl)phenoxymethyl!-3-hydroxy 
quinuclidine hydrochloride as a colourless solid (0.56 g), m.p. 
157.degree.-160.degree. C.; microanalysis, found: C, 61.2; H, 6.8; N, 
10.6%; C.sub.20 H.sub.25 N.sub.3 O.sub.3. HCl requires: C, 61.3; H, 6.7; 
N, 10.7%; NMR: 1.6-2.0(3H,m), 2.1-2.5(2H,m), 2.3-2.4(3H,s), 
3.0-3.45(6H,m), 3.4-3.55(2H,d), 4.1-4.3(2H,q), 5.0-5.2(2H,m), 
5.3-5.8(1H,br), 5.9-6.1(1H,m), 7.15-7.25(1H,d), 7.8-7.9(1H,s), 
7.9-8.0(1H,d). 10.6-10.9(1H,s); m/z 356 (M+H). 
The 
3-2-allyl-4-(3-methyl-1,2,4-oxadiazol-5-yl)phenoxymethyl!-3-hydroxyquinuc 
lidine borane complex used as starting material was prepared as follows. 
A mixture of ethyl 4-hydroxy benzoate (154 g), anhydrous potassium 
carbonate (141 g), allyl bromide (80 ml) and acetone (350 ml) was heated 
at reflux for 17 hours. The reaction mixture was cooled to ambient 
temperature, filtered and the filtrate was evaporated. The residue was 
dissolved in diethyl ether (1 l) and the solution was washed successively 
with aqueus 2M aqueous sodium hydroxide solution (3.times.100 ml), water 
(3.times.250 ml), dried (Na.sub.2 SO.sub.4) and evaporated to give ethyl 
4-allyloxybenzoate as an oil (171 g), NMR (CDCl.sub.3): 1.3-1.4(3H,t), 
4.3-4.4(2H,q), 4.55-4.65(2H,m), 5.25-5.5(2H,m), 5.95-6.15(1H,m), 
6.9-7.0(2H,d) and 7.95-8.05(2H,d). 
Acetamide oxime hydrochloride (10.9 g) was added portionwise to a stirred, 
ice-cooled, suspension of sodium hydride (60% w/w dispersion in mineral 
oil, 7.9 g; the oil was removed by washing the solid with petroleum ether) 
in dry tetrahydrofuran (250 ml) under an atmosphere of argon, whilst 
maintaining the temperature at 5.degree. C. The mixture was stirred at 
5.degree. to 10.degree. C. for 40 minutes. 
Freshly ground 4A molecular sieve (40 g) and a solution of ethyl 
4-allyloxybenzoate (15.6 g) in dry tetrahydrofuran (50 ml) was then added 
to the mixture. The mixture was stirred for 2 days at ambient temperature. 
The mixture was filtered through diatomaceous earth and the filtercake was 
extracted with ethyl acetate (3.times.100 ml). The tetrahydrofuran 
filtrate and ethyl acetate washings were combined and evaporated. The 
residue was dissolved in ethyl acetate (250 ml). The solution was washed 
with water (2.times.100 ml), dried (Na.sub.2 SO.sub.4) and evaporated. The 
residue was triturated with pentane to give a solid (6.6 g) which was 
purified by column chromatography on silica gel (Merck 7736) using 
dichloromethane as eluent, to give, after recrystallisation from 
cyclohexane, 5-(4-allyloxyphenyl)-3-methyl-1,2,4-oxadiazole as a solid 
(4.9 g), m.p. 52.degree.-54.degree. C.; microanalysis, found: C, 66.8; H, 
5.6; N, 12.9%; C.sub.12 H.sub.12 N.sub.2 O.sub.2 requires: C, 66.7; H, 
5.6; N, 13.0%; NMR (CDCl.sub.3): 2.4-2.5(3H,s), 4.6-4.65(2H,m), 
5.3-5.5(2H,q), 5.95-6.05(1H,m), 6.95-7.05(2H,d) and 8.0-8.1(2H,d); m/z 
217(M+H). 
5-(4-allyloxyphenyl)-3-methyl-1,2,4-oxadiazole (1.2 g) and diphenyl ether 
(5 ml) were warmed gently to give a solution. This stirred solution, under 
an atmosphere of argon, was immersed in an oil bath at 265.degree. C. for 
12 minutes. This procedure was repeated three times. The deep red 
solutions were combined, diluted with diethyl ether (100 ml) and extracted 
with aqueous 1M sodium hydroxide (3.times.20 ml). The alkaline extracts 
were combined, washed with ether (3.times.30 ml), cooled in ice-water, 
acidified with aqueous 5M hydrochloric acid (15 ml), and extracted with 
ether (3.times.60 ml). The ether extracts were combined, washed with 
saturated brine (25 ml), dried (Na.sub.2 SO.sub.4) and evaporated. The 
residue was purified by flash column chromatography on silica gel using 
20% ethyl acetate/n-pentane as eluent, to give 
2-allyl-4-(3-methyl-1,2,4-oxadiazol-5-yl)phenol as a solid m.p. 
135.degree.-137.degree. C.; microanalysis, found: C, 66.7; H, 5.8; N, 
12.5%; C.sub.12 H.sub.12 N.sub.2 O.sub.2 requires: C, 66.7; H, 5.6; N, 
13.0%; NMR: 2.3-2.35(3H,s), 3.3-3.4(2H,d), 5.0-5.15(2H,m), 5.85-6.1(1H,m), 
6.95-7.05(1H,d), 7.75-7.8(2H,m) and 10.4-10.5(1H,s); m/z 217 (M+H). 
A mixture of 2-allyl-4-(3-methyl-1,2,4-oxadiazol-5-yl)phenol (0.7 g), 
3-methylenequinuclidine oxide borane complex (0.5 g) and powdered 
potassium carbonate (0.9 g) in dry dimethylformamide (10 ml) was stirred 
at 70.degree. C. for 4 hours. The mixture was poured into water (100 ml) 
and extracted with ethyl acetate (3.times.70 ml). The ethyl acetate 
extracts were combined, washed with water (4.times.30 ml), dried (Na.sub.2 
SO.sub.4) and evaporated. The residue was purified by flash column 
chromatography on silica gel using successively dichloromethane, pentane 
and 50% diethyl ether/pentane as eluent to remove impurities; then using 
diethyl ether as eluent to give 
3-2-allyl-4-(3-methyl-1,2,4-oxadiazol-5-yl)phenoxymethyl!-3-hydroxy 
quinuclidine borane complex as a solid (0.8 g), m.p. 
133.degree.-135.degree. C.; NMR(CDCl.sub.3): 0.6-2.5(3H,br), 
1.6-1.75(1H,m), 1.7-1.9(2H,m), 2.2-2.4(2H,m), 2.45(3H,s), 2.7(1H,s), 
2.7-3.3(6H,m), 3.4-3.5(2Hd), 3.95-4.15(2H,q), 4.95-5.2(2H,m), 
5.85-6.1(1H,m), 6.9-7.0(1H,d), 7.9-7.95(1H,s) and 7.95-8.05(1H,d). 
EXAMPLE 39 
The procedure described in Example 38 was repeated using 
3-2-allyl-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenoxymethyl!-3-hydroxyquinuc 
lidine borane complex (0.85 g) instead of 
3-2-allyl-4-(3-methyl-1,2,4-oxadiazol-5-yl)phenoxymethyl!-3-hydroxyquinuc 
lidine borane complex. There was thus obtained, after recrystallisation 
from isopropanol, 
3-2-allyl-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenoxymethyl!-3-hydroxyquinuc 
lidine hydrochloride as a solid (0.60 g), m.p. 133.degree.-135.degree. C.; 
NMR: 1.55-2.05(3H,m), 2.1-2.4(2H,m), 2.6-2.7(3H,s), 3.0-3.4(6H,m), 
3.4-3.5(2H,d), 4.05-4.3(2H,q), 5.0-5.2(2H,m), 5.5-5.65(1H,s), 
5.9-6.1(1H,m), 7.1-7.2(1H,d), 7.7-7.8(1H,s), 7.8-7.9(1H,d); m/z 356(M+H). 
The 
3-2-allyl-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenoxymethyl!-3-hydroxyquinuc 
lidine borane complex used as starting material was prepared as follows. 
A solution of 2-allyl-4-cyanophenol (5.5 g), hydroxylamine hydrochloride 
(8.5 g) and sodium carbonate (6.1 g) in aqueous ethanol was heated at 
reflux for 3 hours. The solution was cooled to ambient temperature and the 
ethanol was removed by evaporation. The solid was collected by filtration, 
dissolved in ethanol and the solution was filtered. The filtrate was 
evaporated and the residual solid was triturated with hexane to give 
3-allyl-4-hydroxybenzamidoxime as a solid (5.5 g), m.p. 144.degree. C. 
The 2-allyl-4-cyanophenol was prepared as follows. 
A solution of 4-cyanophenol (50 g), allyl bromide (27.2 ml) potassium 
carbonate (47.8 g) in acetone (100 ml) was heated at reflux for 16 hours. 
The reaction mixture was evaporated, water was added to the residue and 
the aqueous mixture was extracted with diethyl ether. The diethyl ether 
extract was washed with dilute aqueous sodium hydroxide solution, dried 
(MgSO.sub.4) and evaporated to give 4-cyanophenyl allyl ether as a solid, 
m.p. 41.6.degree. C.; microanalysis, found: C 75.1; H, 5.8; N, 8.7%; 
C.sub.10 H.sub.9 NO.sub.2 requires: C, 75.5; H, 5.7; N, 8.8%; NMR: 
4.55-4.65(2H,m), 5.2-5.4(2H,m), 5.9-6.05(1H,m), 7.0-7.1(2H,m) and 
7.65-7.75(2H,m). 
A solution of allyl 4-cyanophenyl ether (12 g) in diphenylether (20 ml) was 
heated at 260.degree. C. for 30 minutes. The reaction mixture was cooled 
to ambient temperature, diethyl ether was added and the mixture was 
extracted with 1M aqueous sodium hydroxide solution. The aqueous phase was 
separated, acidified with 2M aqueous hydrochloric acid solution and 
extracted with diethyl ether. The organic phase was separated, dried 
(MgSO.sub.4) and evaporated to give 2-allyl-4-cyanophenol as a solid (11.4 
g), m.p. 70.degree. C.; microanalysis, found: C, 73.7; H, 5.6; N, 9.2%; 
C.sub.10 H.sub.9 NO. 0.25H.sub.2 O requires: C, 73.4; H, 5.8; N, 8.6%; 
NMR: 3.2-3.5(2H,d), 5.0-5.1(2H,m), 5.85-6.05(1H,m), 6.9-7.0(1H,d), 
7.4-7.5(2H,m) and 10.6(1H,s). 
Acetyl chloride (2.28 ml) was added dropwise to a solution of 
3-allyl-4-hydroxybenzamidoxime (5.4 g) in pyridine (48 ml). The solution 
was heated at reflux for 16 hours, cooled to ambient temperature and 
evaporated. The residue was dissolved in ethyl acetate and the solution 
was washed with saturated aqueous sodium carbonate solution, dried 
(MgSO.sub.4) and evaporated, to give 
2-allyl-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenol as a low-melting solid 
(3.8 g), m/z 217 (M+H). 
The procedure described in Example 38 was repeated using 
2-allyl-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenol instead of 
2-allyl-4-(3-methyl-1,2,4-oxadiazol-5-yl)phenol. There was thus obtained, 
after flash column chromatography on silica gel using a gradient of 0 to 
2% ethyl acetate/dichloromethane as eluent, 
3-2-allyl-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenoxymethyl!-3-hydroxyquinuc 
lidine borane complex as a colourless solid, m.p. 132.degree.-135.degree. 
C. eff; NMR(CDCl.sub.3): 0.7-2.3(3H,br), 1.6-1.75(1H,m), 1.75-1.9(2H,m), 
2.2-2.4(2H,m), 2.6-2.7(3H,s), 2.7-2.8(1H,s), 2.8-3.3(6H,m), 3.4-3.5(2H,d), 
3.95-4.15(2H,q), 4.95-5.15(2H,m), 5.9-6.1(1H,m), 6.85-6.95(1H,d), 
7.85-7.9(1H,s) and 7.9-8.0(1H,d). 
EXAMPLE 40 
The procedure described in Example 38 was repeated using 
(E)-3-4-(3-methyl-1,2,4-oxadiazol-5-yl)-2-propenylphenoxymethyl!-3-hydrox 
yquinuclidine borane complex instead of 
3-2-allyl-4-(3-methyl-1,2,4-oxadiazol-5-yl)phenoxymethyl!-3-hydroxy 
quinuclidine borane complex. There was thus obtained 
(E)-3-4-(3-methyl-1,2,4-oxadiazol-5-yl)-2-propenylphenoxymethyl!-3-hydrox 
yquinuclidine hydrochloride as a solid, m.p. 160.degree.-162.degree. C.; 
microanalysis, found: C, 59.8; H, 6.9; N, 10.3%; C.sub.20 H.sub.25 N.sub.3 
O.sub.3. HCl. 0.5 H.sub.2 O requires: C, 59.9; H, 6.8; N, 10.5%; NMR: 
1.6-1.8(1H,m), 1.8-2.05(5H,m), 2.15-2.35(2H,m), 2.35-2.5(3H,s), 
3.0-3.4(6H,m), 4.1-4.3(2H,q), 5.6-5.65(1H,s), 6.35-6.55(1H,m), 
6.7-6.85(1H,d), 7.2-7.3(1H,d), 7.9-8.0(1H,d), 8.05-8.1(1H,s)1 m/z 356 
(M+H). 
The 
(E)-3-4-(3-methyl-1,2,4-oxadiazol-5-yl)-2-propenylphenoxymethyl!-3-hydrox 
yquinuclidine borane complex used as starting material was prepared as 
follows. 
Acetamide oxime hydrochloride (0.44 g) was added in one portion to a 
stirred suspension of sodium hydride (60% w/w dispersion in mineral oil, 
0.32 g; the oil was removed by washing the solid with petroleum ether) in 
dry tetrahydrofuran (20 ml) under an atmosphere of argon. The mixture was 
stirred at ambient temperature for 30 minutes. 
4A molecular sieve (3.2 g) and a solution of 
(E)-3-(4-ethoxycarbonyl-2-propenylphenoxymethyl)-3-hydroxyquinuclidine 
borane complex (1.44 g) in dry tetrahydrofuran (20 ml) was then added to 
the mixture. The mixture was stirred for 4 hours at 60.degree. C. The 
mixture was poured into water (70 ml) and the mixture was extracted with 
ethyl acetate (3.times.70 ml). The ethyl acetate extracts were combined, 
washed with water (3.times.25 ml), dried (NaSO.sub.4) and evaporated. The 
residue was purified by flash column chromatography on silica gel using 
25% ethyl acetate/n-pentane as eluent to give 
(E)-3-4-(3-methyl-1,2,4-oxadiazol-5-yl)-2-propenylphenoxymethyl!-3-hydrox 
yquinuclidine borane complex as a solid (0.55 g), m.p. 
160.degree.-163.degree. C.; NMR(CDCl.sub.3): 0.7-2.2(3H,br), 
1.5-1.9(3H,m), 1.9-2.05(3H,d), 2.2-2.5(2H,m), 2.4-2.5(3H,s), 
2.6-2.65(1H,s), 2.8-3.3(6H,m), 4.0-4.15(2H,q), 6.3-6.45(1H,m), 
6.55-6.65(1H,d), 6.9-7.0(1H,d), 7.9-8.0(1H,d) and 8.15-8.2(1H,s). 
EXAMPLE 41 
A mixture of 3-(2-tri-n-butylethenylstannane)-3-hydroxyquinuclidine (E/Z, 
85:15) (0.88 g), 3-iodo-5-ethyl-1,2,4-oxadiazole (0.93 g), 
tris(dibenzylidine acetone) dipalladium (0) (0.1 g) and cuprous iodide 
(0.1 g) and anhydrous dimethyl formamide (6 ml) was stirred under an 
atmosphere of argon. The reaction mixture was heated at 90.degree. C. for 
2 hours. The reaction mixture was cooled to ambient temperature, diluted 
with methylene chloride (150 ml) and washed with 10% aqueous sodium 
carbonate solution (4.times.25 ml). The organic extracts were combined, 
dried (MgSO.sub.4), and evaported. The residue was purified by column 
chromatography on silica gel using a 90:10:0.5 (v/v/v) mixture of 
methylene chloride, methanol and ammonia as eluent to give a residue which 
was triturated with ethyl acetate to give 
3-2-(E)-(4-5-ethyl-1,2,4-oxadiazol-3-yl!phenyl)ethenyl!-3-hydroxy 
quinuclidine as a solid, m.p. 158.degree.-160.degree. C.; NMR: 
1.13-1.60(5H,m), 1.70(2H,br), 1.98(1H,m), 2.55-3.10(8H,m), 4.62(1H,s), 
6.63-6.83(2H,q), 7.60-7.96(4H,q) 
The 3-(2-tri-n-butylethenyl stannane)-3-hydroxyquinuclidine used as 
starting material was obtained as follows. 
A mixture of 3-ethynyl-3-hydroxyquinuclidine (0.75 g), tri-n-butyl tin 
hydride (1.48 ml) and of .alpha..alpha.'-azo-isobutyronitrile (0.02 g) was 
heated at 100.degree. C. for 10 minutes. The residue was purified by 
column chromatography on silica-gel using a 90:10:0.5 (v/v/v) mixture of 
dichloromethane, methanol and ammonia as eluent to give 
3-(2-tri-n-butylethenyl stannane)-3-hydroxyquinuclidine as a solid, m.p. 
62.degree.-3.degree. C.; microanalysis, found: C, 56.0; H, 9.7; N, 3.0%; 
C.sub.21 H.sub.41 NOSn 0.5 CH.sub.3 OH requires: C, 56.4; H, 9.3 N 3.1%; 
NMR: 0.88(9H,m), 0.8-2.0(23H,m), 2.5-2.9(6H,m), 4.04(1H,s) and 6.12(2H,m); 
m/z 444(M+H). 
EXAMPLE 42 
The procedure described in Example 41 was repeated but using 
3-iodo-5-isopropyl-1,2,4-oxadiazole in place of 
3-iodo-5-methyl-1,2,4-oxadiazole to give 
3-2-(E)-(4-5-isopropyl-1,2,4-oxadiazol-3-yl!phenyl)ethenyl!-3-hydroxy 
quinuclidine as a solid, m.p. 142.degree.-144.degree. C.; NMR: 
1.1-1.58(8H,m), 1.7(2H,br), 1.9-2.1(1H,br), 2.6-2.93(6H,m), 
3.25-3.46(1H,m), 4.8(1H,s), 6.63-6.83(2H,q) and 7.6-7.96(4H,q). 
EXAMPLE 43 
The procedure described in Example 1 was repeated but using 
5-methyl-3-(3-allyl-4-trifluoromethylsulphonyloxyphenyl)-1,2,4-oxadiazole 
in place of 3-(4-bromophenyl)pyridine. There was thus obtained, after 
purification by flash column chromatography on silica gel using 10% 
methanol in dichloromethane containing 1% ammonia followed by 
recrystallisation from acetonitrile, 
3-2-(2-allyl-4-(5-methyl-1,2,4-oxadiazol-5-yl)ethynyl!-3-hydroxyquinuclid 
ine as a solid, m.p. 135.degree.-137.degree. C., NMR: 1.2-2.0(5H,m), 
2.55(3H,s), 3.0(2H,m), 3.6(2H,d), 5.1(1H,br.s), 5.15(1H,m), 5.7(1H,m), 
5.9-6.1(1H,m), 7.55(1H,d) and 7.85(2H,m). 
The 
5-methyl-3-(3-allyl-4-trifluoromethylsulphonyloxyphenyl)-1,2,4-oxadiazole 
was prepared as follows. 
Triflic anhydride (1.4 ml) was added dropwise to a stirred solution of 
5-methyl-3-(3-allyl-4-hydroxyphenyl)1,2,4-oxadiazole (1.2 g) in pyridine 
(10 ml) cooled in an ice-bath. The mixture was stirred for 45 minutes. The 
mixture was diluted with 1M aqueous hydrochloric acid (200 ml) and 
extracted with ethyl acetate (200 ml). The organic extract was washed with 
1M aqueous hydrochloric acid, aqueous sodium bicarbonate solution, and 
brine, then dried (MgSO.sub.4), and evaporated to give 
5-methyl-3-(3-allyl-4-trifluoromethylsulphonyloxyphenyl)-1,2,4-oxadiazole 
(1.37 g) as a solid, NMR: 8.1(2H,m), 7.6(1H,d), 6.1-5.9(1H,m), 
5.3-5.1(2H,m), 3.55(2H,d) and 2.7(3H,s); m/z 351 (M+H). 
EXAMPLE 44 
The procedure described in Example 4 was repeated using 
3-(4-iodophenyl)-5-methyl-1,2,4-oxadiazole in place of 
3-(4-bromophenyl)pyridine to give 
3-2-(4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)ethenyl!-3-hydroxyquinuclidi 
ne which was purified by flash column chromatography on silica gel using a 
gradient of 10% to 20% methanol in dichloromethane containing 1% ammonia 
(density, 0.88 g/cm.sup.3) followed by recrystallisation from acetone to 
give a solid with m.p. 188.degree.-189.degree. C.; NMR: 1.28(1H,m), 
1.5(1H,m), 1.72(2H,m), 2.02(1H,m), 2.7(8H,m), 2.9(1H,d), 4.8(1H,s), 
6.67(1H,d), 6.8(1H,d), 7.63(2H,d) and 7.95(2H,d). 
EXAMPLE 45 
A mixture of 
3-2-(4-(5-methyl-1,2,4-oxadiazole-3-yl)phenyl)ethynyl!-3-hydroxyquinuclid 
ine (0.61 g) and 5% Pd on carbon (60 mg) in ethanol (100 ml) was 
hydrogenated at atmospheric pressure for 4 hours. The mixture was filtered 
and the filtrate was evaporated. The residue was purified by flash 
chromatography on silica gel eluting with 10% methanol in dichloromethane 
containing 1% ammonia (density, 0.88 g/cm.sup.3), to give 
3-2-(4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)ethyl!-3-hydroxyquinuclidine 
(0.15 g) as a solid, m.p. 165.degree.-167.degree. C.; NMR: 1.2-2.1(7H,m), 
2.9-2.65(8H,m), 2.65(3H,s), 4.5(1H,s), 7.4(2H,d) and 7.9(2H,d); m/z 314 
(M+H). 
EXAMPLE 46 
A solution of 3-aminoquinuclidine (187 mg) and 4-(3-pyridyl)benzaldehyde 
(272 mg) in toluene (50 ml) was heated at reflux for 4 hours using a Dean 
and Stark water separator. The toluene was evaporated and the residue 
dissolved in methanol (30 ml). Sodium borohydride (112 mg) was added and 
the mixture stirred for 2 hours. The methanol was evaporated and 1M 
aqueous hydrochloric acid (10 ml) added and made basic by adding sodium 
hydroxide solution (1.35 g/cm.sup.3). The mixture was extracted with 
diethyl ether (3.times.20 ml) and the combined extracts dried (Na.sub.2 
SO.sub.4) and evaporated. The residue was treated with excess of ethereal 
hydrogen chloride solution and the precipitate crystallised from 
methanol/ethyl acetate to give 
3-4-(3-pyridyl)phenylmethylamino!quinuclidine hydrochloride as a 
colourless solid (405 mg), m.p. 266.degree.-268.degree. C.; microanalysis, 
found: C 56.2; H, 6.6; N, 10.0%; C.sub.19 H.sub.23 N.sub.3. 3HCl requires: 
C, 56.6; H, 6.5 N, 10.4%; NMR(DMSO-d.sub.6 /CD.sub.3 CO.sub.2 D): 
1.68-2.10(3H,m), 2.65(1H,m), 3.12-3.38(3H,m), 3.44-3.65(2H,m), 3.70(3H,t), 
3.68-3.90(1H,m), 4.38(2H,s), 7.84-8.00(4H,m), 8.00-8.10(1H,m), 8.78(1H,d), 
8.86(1H,d) and 9.20(1H,s). 
The starting aldehyde was obtained as follows: Diethyl 3-pyridylborane 
(1.51 g), powdered potassium hydroxide (1.71 g) and teteramethylammonium 
bromide (330 mg) were added to a solution of tetrakistriphenylphosphine 
palladium 0! (528 mg) and 4-bromobenzaldehyde dimethyl acetal (3.55 g) in 
anhydrous tetrahydrofuran (60 ml). The mixture was heated at reflux for 2 
hours, the THF evaporated and the residue dissolved in ether (200 ml). The 
ether solution was washed with saturated brine (2.times.100 ml), dried 
(Na.sub.2 SO.sub.4) and evaporated to an oil. The oil was purified by 
column chromatography on alumina, eluting with 10% ethyl acetate in hexane 
to give 4-(3-pyridyl)benzaldehyde dimethyl acetal (1.72 g). 
NMR(CDCl.sub.3): 3.37(6H,s), 5.45(1H,s), 7.45(1H,m), 7.58(4H,m), 
7.89(1H,m), 8.59(1H,dd) and 8.85(1H,d). This diacetal (5.0 g) was stirred 
in 1M aqueous hydrochloric acid (30 ml) for 45 minutes and the mixture 
neutralised with 1M aqueous sodium hydroxide solution (30 ml) and 
extracted with ether (3.times.60 ml). The ether extracts were combined, 
washed with saturated brine, dried (Na.sub.2 SO.sub.4) and evaporated to 
give 4-(3-pyridyl)benzaldehyde (3.41 g) as an oil which gave a solid on 
standing, m.p 48.degree.-51.degree. C.; NMR(CDCl.sub.3): 7.43(1H,q), 
7.76(2H,m), 7.92(1H,m), 8.01(2H,m), 8.65(1H,dd), 8.90(1H,d) and 
10.09(1H,s). 
EXAMPLE 47 
A mixture of 3-(4-iodophenyl)-5-methyl-1,2,4-oxadiazole (1.43 g), 
3-vinylquinuclidine (685 mg), bis(triphenylphosphine)palladium (II) 
chloride (175 mg), copper (I) iodide (90 mg) and triethylamine (5.0 ml) in 
dry dimethylformamide (10 ml) was stirred under argon at 100.degree. C. 
for 5 hours. The dimethylformamide and triethylamine were removed by 
evaporation. The residue was treated with 2M aqueous sodium hydroxide 
solution (20 ml) and extracted with dichloromethane (3.times.20 ml). The 
organic extracts were washed with water (20 ml), dried (MgSO.sub.4) and 
evaporated. The residue was purified by flash column chromatography on 
silica gel using 5% methanol in dichloromethane containing 0.5% ammonia 
(density, 0.88 g/cm.sup.3) as eluent to give 
E-3-2-{4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl}ethenyl!quinuclidine (150 
mg) as a solid, m.p. 93.degree.-97.degree. C.; NMR: 1.4(1H,m), 1.65(2H,m), 
1.8(2H,m), 2.55(1H,m), 2.65(3H,s), 2.8(4H,m), 3.08(1H,m), 3.45(1H,m), 
6.5(1H,d), 6.62(1H,d,d), 7.6(2H,d) and 7.82(2H,d). 
EXAMPLE 48 
A mixture of 3-ethynyl-3-hydroxyquinuclidine (1.06 g), 
2-(4-bromopbenyl)-1,3,4-oxadiazole (1.58 g), 
bis(triphenylphosphine)palladium (II) chloride (245 mg), copper (I) iodide 
(123 mg), triethylamine (7 ml) and dimethylformamide (14 ml) were heated 
at 65.degree. C. under an atmosphere of argon for 4 hours. The 
triethylamine and DHF were removed by evaporation. An aqueous solution of 
sodium hydroxide (2M, 20 ml) was added to the residue and the mixture 
extracted with dichloromethane (3.times.30 ml). The organic extracts were 
combined, dried (MgSO.sub.4) and evaporated. The residue was purified by 
flash column chromatography on silica gel eluting with 10% methanol in 
dichloromethane containing 1% ammonia (density 0.88 g/cm.sup.3) to give 
3-2-(4-1,3,4-oxadiazol-2-yl!phenyl)ethynyl!-3-hydroxyquinuclidine (811 
mg) as a solid, m.p. 229-230%; microanalysis, found: C, 67.9; H, 5.8; N, 
14.2%; C.sub.17 H.sub.17 N.sub.3 O.sub.3. 0.4 H.sub.2 O requires: C, 67.5; 
H, 5.9; N, 13.9; NMR: 1.20-1.44(1H,m), 1.50-1.71(1H,m), 1.77-2.04(3H,m), 
2.69(4H,t), 2.79-2.94(1H,d), 3.04-3.20(1H,d), 5.69(1H,s), 7.63(2H,d), 
8.03(2H,d), 9.35(1H,s); m/z 296(M+H). 
The 2-(4-bromophenyl)-1,3,4-oxadiazole used as starting material was 
obtained as follows: 
A mixture of 4-bromobenzoylhydrazine (3.23 g) and triethylorthoformate (25 
ml) was heated at reflux for 30 hours. The mixture was evaported to give a 
solid (1.69 g) which was used without further purification; NMR: 
7.68(2H,d), 7.95(2H,d), 8.48(1H,s); m/z 225(M+H). 
EXAMPLE 49 
A mixture of 3-ethynyl-3-hydroxyquinuclidine (0.3 g), 
2-methyl-5-(4-bromophenyl)tetrazole (0.48 g), 
bis(triphenylphosphine)-palladium (II) chloride (70 mg), copper (I) iodide 
(35 mg), triethylamine (1 ml) and dimethylformamide (2 ml) was stirred at 
70.degree. C. for 2 hours. The mixture was diluted with dichloromethane (4 
ml) and filtered down a short column of silica (Varian Bond-sluts S1 
silica) eluting with a gradient of 0:100 (v/v) to 100:0 (v/v) 
methanol/dichloromethane. The appropriate organic fractions were combined, 
washed with saturated aqueous sodium carbonate (3.times.30 ml), dried 
(Na.sub.2 CO.sub.3) and evaporated to give 
3-2-(4-2-methyl-tetrazol-5-yl!phenyl)ethynyl!-3-hydroxyquinuclidine (260 
mg) as a solid, m.p. 228.degree.-230.degree. C.; microanalysis, found: C, 
65.9; H, 6.1; N, 22.2%; C.sub.17 H.sub.19 N.sub.5 O requires: C, 66.0; H, 
6.2; N, 22.6%; NMR: 1.2-1.4(1H,m), 1.5-1.7(1H,m), 1.8-2.0(3H,m), 
2.7(4H,m), 2.8-3.2(2H,m), 4.4(3H,s), 5.6(1H,s), 7.6(2H,m), 8.05(2H,m); m/z 
310(M+H). 
The 2-methyl-5-(4-bromophenyl)tetrazole used as starting material was 
obtained as described in Perkin, Trans II, (1984), 721 (also R. N. Butler 
et al, J. Chem. Res. 5, (1981) 174). 
EXAMPLE 50 
Illustrative pharmaceutical dosage forms suitable for presenting the 
compounds of the invention for therapeutic or prophylactic use include the 
following tablet and capsule formulations, which may be obtained by 
conventional procedures well known in the art of pharmacy and are suitable 
for therapeutic or prophylactic use in humans: 
______________________________________ 
(a) Tablet I mg/tablet 
Compound Z* 1.0 
Lactose Ph. Eur. 93.25 
Croscarmellose sodium 4.0 
Maize starch paste (5% w/v aqueous paste) 
0.75 
Magnesium stearate 1.0 
(b) Tablet II mg/tablet 
Compound Z* 50 
Lactose Ph. Eur 223.75 
Croscarmellose sodium 6.0 
Maize starch 15.0 
Polyvinylpyrrolidone (5% w/v aqueous paste) 
2.25 
Magnesium stearate 3.0 
(c) Tablet III mg/tablet 
Compound Z* 100 
Lactose Ph. Eur. 182.75 
Croscarmellose sodium 12.0 
Maize starch paste (5% w/v aqueous paste) 
2.25 
Magnesium stearate 3.0 
(d) Capsule mg/capsule 
Compound Z* 10 
Lactose Ph. Eur. 488.5 
Magnesium stearate 1.5 
______________________________________ 
Note 
*The active ingredient Compound Z is a compound of formula I, or a salt 
thereof, for example a compound of formula I described in any of the 
preceding Examples. 
The tablet compostions (a)-(c) may be enteric coated by conventional means, 
for example, with cellulose acetate phthalate 
##STR2##