WO1995035295A1

WO1995035295A1 - Quinuclidine derivatives as squalene synthase inhibitors

Info

Publication number: WO1995035295A1
Application number: PCT/GB1995/001362
Authority: WO
Inventors: George Robert Brown; Paul Robert Owen Whittamore; David Robert Brittain
Original assignee: Zeneca Limited
Priority date: 1994-06-17
Filing date: 1995-06-12
Publication date: 1995-12-28
Also published as: GB9412145D0

Abstract

Compounds of formula (I) wherein R1 is hydrogen or hydroxy; R2 is hydrogen; or R?1 and R2¿ are joined together so that CR1 -CR2 is a double bond; X is selected from -CH¿2?CH2-, -CH = CH-, -C ≡ C-, -CH2O-, -CH2NH-, -NHCH2-, -CH2CO-, -COOH2-, -CH2S(O)n- and -S(O)nCH2- (wherein n is 0,1 or 2); Ar is phenyl which bears one or more substituents independently selected from the groups alkyl, alkenyl, alkynyl, alkoxy, alkoxycarbonyl, alkoxycarbonylalkyl, alkoxyalkyl, alkylamino, di-[alkyl]amino, carbamoyle, alkylcarbamoyl, di-[alkyl]carbamoyl, alkanoyl and oxime derivatives thereof and 0-alkyl ethers of said oximes, alkylthio, alkylsulphinyl and alkylsulphonyl when substituted by one or more groups selected from heterocyclyl, heterocyclyloxy and heterocyclyloxycarbonyl; or Ar is phenyl which bears one or more heterocyclyloxy groups; and wherein Ar and/or a phenyl or heterocyclyl moiety in any of said groups mentioned above may further be substituted; and their pharmaceutically acceptable salts inhibits squalene synthase and are hence useful in lowering cholesterol levels in blood plasma. Processes for preparing compounds of formula (I) are also referred to as well as pharmaceutical compositions containing them and their use in medicine.

Description

HETEROCYCLES

This invention concerns heterocyclic derivatives 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 derivatives 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.

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 US Patent 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 results in an upregulation of the hepatic 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 (FPP) 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.

The present invention is based on the discovery that certain heterocyclic derivatives 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:

R¹ is hydrogen or hydroxy;

R² is hydrogen; or

R¹ and R² are joined together so that CR¹-CR² is a double bond;

X is selected from -CH₂CH₂-, -CH=CH-, -C≡C-, -CH₂O-, -CH₂NH-, -NHCH₂-,

-CH₂CO-, -COCH₂-, -CH₂S(O)_n- and -S (O)_nCH₂ (wherein n is 0, 1 or 2);

Ar is phenyl which bears one or more substituents independently selected from the groups (1-6C) alkyl, (2-6C) alkenyl,

(2 -6C) alkynyl, (1-6C) alkoxy, (1-6C) alkoxycarbonyl,

(1-6C) alkoxycarbonyl (1-6C) alkyl, (1-6C) alkoxy (1-6C) alkyl,

(1-6C) alkylamino, di-[(1-6C) alkyl]amino, carbamoyl,

(1-6C) alkylcarbamoyl, di-[(1-6C)alkyl]carbamoyl,

(1-6C) alkanoyl and oxime derivatives thereof and 0-(1-6C)alkyl ethers of said oximes, (1-6C)alkylthio, (1-6C) alkylsulphinyl and

(1-6C) alkylsulphonyl when substituted by one or more groups selected from heterocyclyl, heterocyclyloxy and heterocyclyloxycarbonyl; or Ar is phenyl which bears one or more heterocyclyloxy groups;

and wherein Ar and/or a phenyl or heterocyclyl moiety in any of said groups mentioned above 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, (1-6C) alkanoylamino, (1-4C) alkylenedioxy, (1-6C) alkanoyl and oxime derivatives thereof and

0-(1-6C)alkyl ethers of said oxime derivatives; provided that when X is -NHCH₂ - or -S(O)_nCH₂- (wherein n is 0,1 or 2), then R¹ is not hydroxy.

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, the present invention includes any tautomeric form of a compound of formula I which possesses the beneficial pharmacological effect of inhibiting squalene synthase.

It will also be understood that, insofar as certain of the compounds of the formula I may exist as geometric isomers the present invention includes any such isomer 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 R¹ and R² are joined so that CR¹-CR² is a double bond, the quinuclidine moeity in formula I will comprise the 2,3-dehydroquinuclidine moiety shown in formula la.

As used herein the term heterocyclyl emcompasses aromatic heterocycles which contain (in addition to carbon atoms) one, two, three or four heteroatoms selected from nitrogen, oxygen and sulphur as well as non-aromatic heterocycles which contain (in addition to carbon atoms) one, two, three or four heteroatoms selected from nitrogen, oxygen and sulphur.

In particular, the term heterocyclyl encompases monocyclic aromatic heterocycles which contains (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; as well as bicyclic

heterocycles which consists of a non-aromatic 5-membered or 6-membered heterocyclic ring containing (in addition to carbon atoms) one, two, three or four heteroatoms selected from nitrogen, oxygen and sulphur which is fused to a benzene ring; and partially or fully hydrogenated derivatives of said monocyclic or bicyclic heterocycles.

Suitable values for heterocyclyl will therefore include, for example, an aromatic 5-membered or 6 -membered heterocyclic ring containing one, two, three or four heteroatoms selected from nitrogen, oxygen and sulphur, and an aromatic 5-membered or 6-membered

heterocyclic ring containing one, two, three or four heteroatoms selected from nitrogen, oxygen and sulphur which is fused to a benzene ring, and partially or fully hydrogenated derivatives thereof.

Suitable values for non-aromatic heterocycyl will also include, in addition to the partially and fully hydrogenated

derivatives mentioned above, piperidino, piperazino, morpholino, thiomorpholino and succinimido.

A particular value for a group which may be present on Ar 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; di-[(1-4C)alkyl] amino, such as 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 alkoxycarbonyl methoxycarbonylmethyl, methoxycarbonylethyl, ethoxycarbonylethyl or ethoxycarbonylmethyl; for alkylthio; methylthio, ethylthio, propylthio,

isopropylthio, or butylthio;

for alkylsulphinyl; methylsulphinyl, ethylsulphinyl,

propylsulphinyl, isopropylsulphinyl or

butylsulphinyl;

for alkylsulphonyl; methylsulphonyl, ethylsulphonyl,

propylsulphonyl, isopropylsulphonyl 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 selcted from methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl and sec-butyl, (in particular fluoromethyl, difluoromethyl or trifluoromethyl);

for alkanoyl; formyl, acetyl, propionyl and butyryl;

for 0-(1-6C) alkyl methyl, ethyl, propyl, isopropyl and butyl ethers of alkanoyl ethers of said oximes;

oximes

for alkenyloxy; allyloxy and propenyloxy;

for (1-4C) alkylenedioxy methylenedioxy, ethylenedioxy and

trimethylenedioxy;

for alkanoylamino; formamido, acetamido, propionamido,

iso-propionamido, butyramido or iso-butyramido; for alkoxyalkyl ethoxyethyl, methoxyethyl, ethoxymethyl and methoxyethyl;

for alkoxyalkoxy; methoxyethoxy, ethoxymethoxy, ethoxyethoxy and methoxymethoxy.

Particular values for heterocyclyl include, for example, furyl, pyrrolyl, thienyl, pyridyl, pyrimidinyl, pyridazinyl,

imidazolyl, oxazolyl, isooxazolyl, thiazolyl, isothiazolyl,

oxadiazolyl, tetrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl,

benzfuranyl, quinolyl, isoquinolyl, benzimidazolyl, indolyl,

benzthiazolyl, benzodioxolyl (such as 1,3-benzodioxolyl),

benzodioxanyl (such as 1,4-benzodioxanyl) and benzodihydrofuranyl; and partially or fully hydrogenated derivatives thereof such as

tetrahydrofuranyl.

Further particular values include, for example, piperidino, piperazino, morpholino, thiomorpholino and succinimido.

In particular Ar is phenyl which bears one or more substituents independently selected from heterocyclyloxy,

heterocyclyl (1-6C) alkyl, heterocyclyloxy (1-6C) alkoxy,

heterocyclyl (1-6C) alkoxycarbonyl, heterocyclylcarbonyl; and, in addition, optionally bears 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, (1-6C) alkanoylamino,

(1-4C) alkylenedioxy, (1-6C) alkanoyl and oxime derivatives thereof and 0-(1-6C) alkyl ethers of said oxime derivatives. In general, for example, it is preferred that Ar bears one, two, three or four substituents.

In particular, X is selected from -C≡C-, -CH=CH, -CH CH -, -CH₂O-, -CH₂S(O)_n- (n=0,1 or 2), -CH₂NH- , -CH₂CO- and -COCH₂; more particularly from -C≡C-, -CH=CH-, -CH₂CH₂-, -CH₂O -CH₂S- and -CH₂NH-.

In general it is preferred, for example, that R¹ is hydroxy and R² is hydrogen.

In general it is preferred, for example, that X is -C≡C-, -CH₂CH₂-, -CH₂ O- or -CH=CH, especially -C≡C- .

In one embodiment of interest heterocyclyl comprises a 5- or 6-membered heteroaryl moiety containing one, two or three heteroatoms selected from nitrogen, oxygen and sulphur. Thus, preferred values for heterocyclcyl include pyridyl, pyrimidinyl and oxadiazoyl.

It is generally preferred, for example that when

heterocyclyl comprises a heteroaryl moiety, it comprises a pyridyl moiety.

Specific values of interest for X include, for example,

-C≡C-, -CH=CH-, -CH₂CH₂- and -CH₂O-.

Specific values for R¹ and R² include, for example, R¹ is hydroxy and R² is hydrogen.

Specific values for a substituent for Ar which includes a heterocyclyl moiety include groups of formula -X-het wherein X is as defined above and het is heteroaryl (especially pyridyl).

Specific values for Ar include, for example, phenyl which bears one or more (particularly one or two) substituents selected from pyridyl (1-6C) alkoxycarbonyl (such as pyridylmethoxycarbonyl),

tetrazolyl (1-6C) alkyl, (such as tetrazolylethyl),

oxadiazolyl (1-6C) alkyl (such as oxadiazolylethyl), pyridyl (1-6C) alkyl, (such as pyridylmethyl), tetrahydrofuranyloxy,

N-succinimido (1-6C) alkoxy (such as N-succimidoethoxy),

pyridyloxy (1-6C) alkoxy (such as pyridyloxyethoxy) and pyridylcarbonyl; and optionally one or more (in particular, one or two) substituents selected from (1-6C) alkyl (such as methyl), (2-6C) alkenyl (such as allyl), halogeno (such as fluoro), 1-6C) alkoxy (such as methoxy) and (1-6C) alkanoyl (such as formyl). In one embodiment of the present invention, R¹ and R² are both hydrogen; and X and Ar have any of the meanings defined above.

In a further embodiment of the present invention, R¹ and R² are joined together so that CR¹-CR² is a double bond; and X and Ar have any of the meanings defined above.

In a further embodiment of the present invention R¹ is hydroxy, R² is hydrogen; and X and Ar have any of the meanings defined above.

In a further embodiment of the invention R¹ is hydroxy; R² is hydrogen; X is selected from -C≡C-, -CH=CH- , -CH₂CH₂-, -CH₂O-,

-CH₂NH-, -CH₂CO-, -COCH₂- and -CH₂S (O)_n (n=o, 1 or 2);

Ar is phenyl which bears one or more substituents independently selected from the groups heterocyclyloxy,

heterocyclcyl (1-6C) alkyl, heterocyclyloxy (1-6C) alkoxy,

heterocyclcyl (1-6C) alkoxycarbonyl and heterocyclylcarbonyl; wherein said heterocyclcyl moiety comprises a monocyclic or bicyclic aromatic heterocycle which contains up to 4 heteroatoms selected from nitrogen, oxygen and sulphur; and wherein Ar and/or a heterocyclyl moiety in any of said groups mentioned above 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-SC) alkylamino,

di-[(1-6C)alkyl]amino N-(1-6C) alkylcarbamoyl,

di-N,N-[(1-6C)alkyl]carbamoyl, (1-SC) alkoxycarbonyl, (1-6C) alkylthio, (1-6C) alkylsulphinyl, (1-6C) alkylsulphonyl, halogeno (1-6C) alkyl, (1-6C) alkanoylamino, (1-4C) alkylenedioxy, (1-6C) alkanoyl and oxime derivatives thereof and 0-(1-6C) alkyl ethers of said oxime

derivatives.

Particular, preferred and specific values include the appropriate values mentioned above.

In a preferred embodiment of the invention R¹ is hydroxy; R² is hydrogen; X is selected from -C≡C- and -CH₂O-;

Ar is phenyl which bears one or more substituents independently selected from the groups mentioned above.

In a specific group of compounds R¹ is hydroxy, R² is hydrogen, X is selected from -CH₂CH₂-, -CH=CH-, -C≡C- and -CH₂O- (especially -C≡C-); Ar is phenyl which bears a

pyridyl (1-6C) alkoxycarbonyl (such as pyridylmethoxycarbonyl), tetrazolyl (1-6C) alkyl (such as tetrazolylethyl),

oxadiazolyl (1-6C) alkyl (such as oxadiazolylethyl), pyridyl (1-6C) alkyl (such as pyridylmethyl), tetrahydrofuranyloxy,

N-succinimido (1-6C) alkoxy (such as N-succinimidoethoxy),

pyridyloxy (1-6C) alkoxy (such as pyridyloxyethoxy) and pyridylcarbonyl; and in addition Ar optionally bears 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-SC) 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, (1-6C) alkanoylamino,

(1-4C) alkylenedioxy, (1-SC) alkanoyl and oxime derivatives thereof and O-(1-6C) alkyl ethers of said oxime derivatives.

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.

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 preferred processes in which the various generic radicals, for example, R¹, R², X and Ar 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 R¹ and R² are both hydrogen, reducing a compound of formula I in which R¹ and R² are joined together so that CR¹-CR² 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, 0-60°C. It may be preferable to cool the reaction below ambient temperature (eg. to about 0°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 0-60°C, and may be accelerated by heating (eg.

refluxing). (b) For compounds of formula I in which R¹ and R² are joined together so that CR¹-CR² is a double bond, dehydrating a compound of formula I in which R is hydroxy and R² is hydrogen.

The dehydration may be carried out using an acid such as sulphuric acid (eg. 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 70-130°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 R¹ and R² are joined together so that CR¹-CR² 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 -OCH2- or -SCH2-.

The compounds of formula II may be prepared from a compound of formula I in which R¹ is hydroxy. For example, where Z is halogen the compound of formula I in which R¹ is hydroxy and R² is hydrogen may be reacted with the appropriate phosphorous halide (eg. PCI₅, PBr₃ or PI₃), or where Z is chloro, by reaction with thionyl chloride. The compound of formula I in which R¹ is hydroxy may be reacted with mesyl chloride to give 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 -CH₂CO-, reacting an organometallic compound of formula III in which M is a metal atom or a derivative thereof, with a compound of formula IV.

Suitable values for M include, for example, magnesium and lithium. In the case where M is magnesiu t 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°C and the reflux temperature of the reaction mixture.

The compounds of formula III may be prepared from the corresponding compound of formula Ar-"hal" in which "hal" is a halogen atom, such as iodo or bromo as is well known in the art.

(e) For those compounds of formula I in which X is -CH₂NH- or -NHCH₂-, reducing a compound of formula I in which X is -CH=N- or -N=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 such as 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 (eg. when X is -NHCH2-), it is generally preferred that a chemical reducing agent is employed.

The compounds of formula I in which X is -CH=N- may be prepared by reaction of a compound of formula V with a compound of formula VI. The reaction is generally carried out in an inert hydrocarbon solvent such as toluene or benzene, with heating (eg. 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=CH- may be prepared by reaction of a compound of formula VII with a compound of formula VIII.

(f) For those compounds of formula I in which X is -CH₂NH-, -CH₂O- or -CH2S-, R¹ is hydroxy and R² is hydrogen, reacting a compound of formula IX in which Z is -NH₂, -OH or SH as appropriate with a compound of formula X.

The reaction is conveniently carried out in a solvent such an inert hydrocarbon eg. toluene with heating. The reaction may be facilitated by the presence of acid or base.

The compound of formula X 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 X 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 halohydrin treated with base (eg. NaOH) to give the compound of formula X.

(g) For compounds of formula I in which X is -CH=CH-, reacting a compound of formula XI with a compound of formula V 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 (eg -40°C to 0°C); and metal hydrides such as sodium hydride in a solvent such as dimethyl formamide or dimethyl suphoxide. A

particularly suitable base is, for example, sodium dimsyl which may conveniently be used in a solvent such as dimethyl sulphoxide. The compounds of formula XI may be prepared by reaction of a compound of formula ArCH₂-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 -CH₂CH₂-, reducing a compound of formula I in which X is -CH=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 ArCH₂CH₂-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 (eg -70°C) in an inert solvent such as

tetrahydrofuran.

(i) For compounds of formula I in which X is -COCH₂-, reacting a compound of formula XII in which M is a metal atom or a derivative thereof, with a compound of formula XIII.

Suitable values for M and suitable reaction conditions are those mentioned in (d) above. The compounds of formula XII may be prepared from the corresponding halogeno compound in a manner analogous to the preparation of compounds of formula III discussed in

(d) above.

(j) For those compounds of formula I in which X is -CH₂O- or

-CH₂S-, reacting a compound of formula XIV with a compound of formula

XV, in which Z is a leaving group and Z is -YM, or Z¹ is -YM and Z 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 20-150°C.

It may be desirable to protect the quinuclidine nitrogen atom during the reaction, especially when Z¹ is -YM, as described in (1) below. It may be desirable to protect R¹ when it represents a hydroxy group as, for example, a silyl ether.

(k) For those compounds of formula I in which X is -SCH₂- and

R¹ and R² are both hydrogen, reacting a compound of formula

XVI in which Y is sulphur with a compound of formula XVII 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, eg sodium or potassium hydroxide, and in a solvent such as dimethyl sulphoxide or dimethylformamide.

(1) For compounds of formula I in which X is -SCH₂-,

-CH₂O-, or -CH₂S-, deprotecting a compound of formula XVIII in which Q is a protecting group.

Suitable values for Q include, for example, -BH or an oxygen atom. When Q is -BH 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 XVIII in which X is -CH₂O- or -CH₂s- may be prepared by methods analogous to those described in (j), and in which X is -SCH₂- 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 XVIII in which X is -CH₂O- or -CH₂S- and R¹ is hydroxy and R² is hydrogen is by a procedure analogous to that described in (f) in which the compound of formula X 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 may be prepared by reaction of the appropriate quinuclidine moiety with BH .THF, generally with cooling (for example at -70°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≡C-, reacting a compound of formula I in which X is -CH=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 (eg. at a temperature between ambient and about 70°C).

(n) For those compounds of formula I in which R¹ is hydroxy,

R² is hydrogen and X is -C≡C-, reacting a compound of formula XIX 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 R¹ and R² are hydrogen and X is -C≡C-, reacting a compound of formula XIX in which M is a metal atom with a compound of formula XV in which Z is a leaving group.

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≡C- and R¹ is hydrogen or hydroxy and R² is hydrogen, reacting a compound of formula XX with a compound of formula IX 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(PPh₃)₂Cl₂. 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 to 100°C). The reaction is preferably carried out in the prersence of copper (I) iodide. Compounds of formula XX may be prepared according to Scheme la and 2b.

(q) For those compounds in which X is -C≡C- and R¹ is hydrogen or hydroxy and R² is hydrogen, reacting a compound of formula XXI with a compound of formula IX 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 XXI may be prepared according to Scheme lb and 2a.

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 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.

In general, it is preferred that the substituents on Ar are introduced before Ar is coupled to the quinuclidine moiety but in some instances it may be appropriate to introduce substituents or modifiy substituents after such coupling. The various substituted phenyl derivatives used as starting materials may, as indicated above, be prepared by methods well known in the art. As particular examples starting materials in which Ar bears an alkoxy group which may be further substitututed as defined above may be prepared by alkylation of the appropriate phenol. Thus a compound of formula Hal-Ar-OH may be reacted with a compound of formula R-hal in the presence of a base and a suitable solvent (Hal are suitable halogen atoms and R

represents remainder of the substituent to be introduced). Compounds in which Ar bears an alkylthio group which may be further substituted may be prepared in an analogous manner. Compounds in which Ar bears an alkoxycarbonylheterocyclyl group may be prepared by esterification of a compound bearing a carboxyheterocyclyl group using the

appropriate alcohol and standard conditions such as acid catalysis (eg. sulphuric acid). An alkynyl group (which may be further

substituted as defined above) may be introduced, for example, by reaction of an appropriate compound of formula Ar-Z in which Z is a suitable leaving group with a compound of formula HCQC-R in which R represents the remainder of the substituent in a similar manner to that described in (p) above. In a similar manner compounds with an alkenyl substiuent (which may be further substituted) may be prepared from a compound of formula Ar-Z and R-CH=CH₂. Compounds having an alkenyl substituent such as allyl and an oxy substituent may be prepared from a compound of formula ArOH by reaction with, for example, allyl bromide followed by a Claisen rearrangement.

When a pharmaceutically-acceptable salt of a compound of the formula I is required, it may be obtained, for example, by reaction of said compound with the appropriate acid (which affords a

physiologically acceptable anion), or with the appropriate base (which affords a physiologically acceptable cation), or by any other conventional salt formation procedure.

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 200μl of a buffered solution containing potassium phosphate (50mM) , MgCl₂ (4.95mM), KF (9.9mH), NADPH (0.9mM) and rat liver microsomal protein (20μg) . 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°C throughout the incubation.

The reaction is started with the addition of the substrate

(1-[³H]-farnesyl pyrophosphate), final concentration 20μM, and stopped after 15 minutes reaction time with the addition of 50μl of 4% KOH.

The reaction products are separated from unreacted substrate after application to a C-18 octadecyl lccBond column (Analytichem Int product No. 617101). An aqueous fraction is eluted with 250μl 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 IC₅₀ (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 IC₅₀ 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 25μM.

By way of illustration of the squalene synthase inhibitory properties of the compounds of formula I, the compound described in Example 4 below gave an inhibition of about 69% at 2.5μM.

(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

14C-acetate. Female rats (35 - 55 g) are housed in reverse lighting conditions (red light from 0200h - 1400h) 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 25μCi [2-¹⁴C]-acetate (NEN DUPONT. specific activity,

45-60mCi/mmol NEC-085H, or AMERSHAM specific activity, 50-60mCi/mmol

CFA 14) in a volume of 0.25 ml saline (100μCi/ml). After a further hour, rats are terminally anaesthetised with halothane and a blood sample obtained from the abdominal vena cava.

lml of plasma is lyophilised and then saponified in 2ml ethanolic KOH (1 part 33% KOH, 9 parts ethanol) at 75°C for 2 hours. After addition of an equal quantity of water, non-saponifiable lipids are extracted with two 5ml volumes of hexane. The hexane extracts are evaporated to dryness and the residues dissolved in ethanol to determine cholesterol specific radioactivity. ED₅₀ values can be determined in the standard way.

An alternative test to measure the ability of a compound to inhibit cholesterol synthesis in vivo uses H-mevalonolactone in place of ¹⁴C-acetate.

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 4 gave an inhibition in cholesterol biosynthesis of about 80%

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 animal (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 and 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 sequestrants, 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.

As inhibitors of squalene synthase the compounds of the present invention may also find utility as antifungal agents. Thus the present invention also provides a method of treating fungal infections comprising administering an effective amount of a compound of formula I, or a salt thereof. In pharmaceutical applications an effective amount of the compound of formula I, or a pharmaceutically acceptable salt, will be administered to a warm blooded animal, such as man.

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 18-26°C;

(iii) yields are given for illustration only and are not

necessarily the maximum attainable by diligent process

development;

(iv) proton NMR spectra were normally determined at 200 MHz using tetramethylsilane (TMS) as an internal standard in DMSOd₆

(unless stated otherwise), 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, multiplet; t, triplet; br, broad; d,

doublet;

(v) all end-products were characterised by microanalysis, NMR and/or mass spectroscopy (molecular ions indicated by m/z

values); and

(vi) conventional abbreviations are used for individual radicals and recrystallisation solvents, for example, Me = methyl,

Et = ethyl, Pr = Propyl, Pr = isopropyl, Bu = butyl, Bu = isobutyl, Ph = phenyl; EtOAc = ethyl acetate, Et20 = ether, MeCN = acetonitrile, MeOH = methanol, EtOH = ethanol, PrⁱOH =2-propanol, H₂O = water.

EXAMPLE 1

Palladium (bis triphenylphosphine) dichloride (130mg) and cuprous iodide (66mg) were added to a stirred solution of

pyridyl-2-methyl 3-(3-allyl-4-trifluoromethylsulphonyloxy- phenyl) propionate (1.57g) and 3-ethynyl-3-hydroxyquinuclidine (540mg) in dimethylformamide under an atmosphere of argon at ambient

temperature. Triethylamine (3.6ml) was added and the reaction mixture heated at 70°C for 7 hours.

The reaction mixture was cooled to ambient temperature. The mixture was diluted with water (100ml) and then extracted with ethyl acetate. The organic phase was washed with saturated sodium bicarbonate solution, dried and evaporated. The residual oil was purified by chromatography on Alumina (Fluka 507C) using a 9:1 (v/v) mixture of ethyl acetate and methanol as eluent to give

3-[2-(2-allyl-4-(2-(2-pyridylmethyloxycarbonyl)ethyl)phenyl)ethynyl]- quinuclidin-3-ol (547mg) as a solid, m.p. 38-40°C; NMR(CDCl3) :

1.41 (1H,m), 1.65 (1H,m), 2.04 (3H,m), 2.38 (1H,bs), 2.73 (2H,t),

2.90 (6H,m), 3.05 (1H,d), 3.32 (1H,d), 3.48 (2H,d), 5.02 (2H,m),

5.20 (2H,s), 5.95 (1H,m), 7.01 (2H,m), 7.26 (3H,m), 7.65 (1H.d. d. d) and 8.58 (1H,m); m/z 431 (M+H).

The pyridyl-2-methyl 3-(3-allyl-4-trifluoromethyl sulphonyloxyphenyl) propionate used as starting material was prepared as follows.

Potassium hydrogen carbonate (0.651g) was added to a suspension of 3-allyl-4-hydroxyphenylpropionic acid (1.343g) in water (5ml) and ethanol (5ml) under an atmosphere at argon at ambient temperature. The mixture was stirred for 1 hour. The mixture was evaporated and the residue azeotroped with toluene then dried under vacuum.

A solution of 2-chloromethyl pyridine (780mg) [prepared by addition of base to the hydrochloride salt of 2-chloromethylpyridine followed by extraction) in N,N-dimethylpropylene urea (3ml) was added to the above potassium salt in N,N-dimethylpropylene urea (4ml). The mixture was stirred at 75°C under an atmosphere of argon for 4 hours. The mixture was cooled to ambient temperature, water (50ml) was added and the aqueous mixture was extracted with ethyl acetate. The organic phase was washed with saturated sodium bicarbonate solution, dried, and evaporated to give an oil. The oil was purified by chromatography on silica gel using a 1:1 (v/v) mixture of ethyl acetate and hexane as eluent to give pyridyl-2-methyl-3-(3-allyl-4-hydroxyphenyl) propionate (1.30g) as a colourless solid, m.p. 74°C; NMR(CDCl3) : 2.67(2H,t), 2.89 (2H,t), 3.38 (2H,d), 5.12 (2H,m), 5.77 (2H,s), 5.78 (1H,d),

5.99 (1H,m), 6.71 (1H,m), 6.92 (2H,m), 7.24 (2H,m), 7.68 (1H, d. d. d) and 8.48 (1H,d); m/z 298 (M+H).

Trifluoromethyl sulphonic anhydride (0.90ml) was added over a period of 5 minutes to a solution of pyridyl-2-methyl 3-(3-allyl- 4-hydroxyphenyl) propionate (1.28g) in pyridine (5ml) under an atmosphere of argon at 0°C. The mixture was stirred for 1 hour at 0°C, and was then allowed to warm to ambient temperature and allowed to stand for 16 hours. Toluene (100ml) was added and the mixture evaporated. The solid residue was treated with water and extracted with ethyl acetate. The ethyl acetate phase was washed with saturated brine; dried (MgSO₄) and evaporated to give an oil. The oil was purified by chromatography on silica gel using a 7:3 (v/v) mixture of hexane and ethyl acetate as eluent to give pyridyl-2-methyl

3-(3-allyl-4-trifluoromethylsulphonyloxyphenyl)propionate (1.60g) as an oil; microanalysis, found: C,53.00; H,3.80; N, 3.20%; C₁₅H₁₇F₃NO₅S requires: C,53.10; H, 4.20; N, 3.26%; m/z 367 (M+H).

EXAMPLE 2

Sodium hydride (182mg) was added to a stirred mixture of acetamidoxime hydrochloride (252mg) in dry tetrahydrofuran (5ml) under an atmosphere of argon. The reaction mixture was stirred for 15 minutes. A solution of 3-trimethylsilyloxy-3-[2-(2-allyl-

4-ethoxycarbonylethylphenyl) ethynyl] quinuclidine (lg) in dry

tetrahydrofuran (5ml) was added dropwise to the reaction mixture followed by 4A molecular sieves 8-12 mesh 1/16" pellets (2g). The reaction mixture was stirred at 60°C under an atmosphere of argon overnight. The reaction mixture was cooled to ambient temperature and filtered. Ethyl acetate was added to the filtrate and the organic mixture was washed with saturated aqueous sodium bicarbonate, brine, dried (MgSO₄) and evaporated. The residue was purified by

chromatography on silica gel (Varian bond elut silica gel) using ethyl acetate followed by a 90:9:1 (v/v/v) mixture of ethyl

acetate/methanol/ammonia, density 0.88/cm as eluent to give

3-trimethylsilyloxy-3-[2-(2-allyl-4-(2-(3-methyl-1,2,4-oxadiazol-5-yl) ethyl) phenyl) ethynyl] quinulidine as an oil (270mg); Microanalysis, found: C, 69.1; H, 7.9; N, 9.40%; C₃₆H₃₅N₃O₂Si requires: C, 69.4; H,

7.85; N, 9.34% NMR [CDCl3] : 0.28 (9H,s), 1.25-1.5 (1H,m),

1.5-1.75 (1H,m), 1.85-2.10 (3H,m + H₂O), 2.37 (3H,s), 2.7-2.9 (4H, m), 3.0-3.2 (5H,m), 3.2-3.4 (1H, dd), 3.5-3.55 (2H, d), 5.0-5.15 (2H, m),

5.9-6.1 (1H,m), 7.0 (2H,m) and 7.3-7.4 (1H, d); m/z 450 (M+H). Further elution gave 3-[2-(2-allyl-4-(2-(3-methyl-1,2,4-oxadiazol-5-yl)ethyl)- phenyl)ethynyl]quinuclidin-3-ol as oil which slowly solidified, microanlysis, found: C, 71.2; H, 7.2; N, 10.1%; C₂₃H₂₇N₃O₂. 0.5 ethyl acetate, requires: C; 71.3; H, 7.4; N, 9.8%; NMR: 1.2-1.48 (1H,m), 1.5-1.7 (1H,m), 1.75-2.0 (3H, m + H2O) , 2.3 (3H,s); 2.5-3.4 (10H,m), 3.4-3.5 (2H,d), 5.0-5.1 (2H,m), 5.5 (1H,s), 5.85-6.0 (1H, m),

7.05-7.15 (2H,m), 7.25-7.3 (1H,m); m/z 378 (M+H).

The 3-trimethyl silyloxy-3-[2-(2-allyl-4- ethoxycarbonylethylphenyl)ethynyl]quinuclidine was prepared in the following manner.

Imidazole (464mg) was added to a solution of

3-hydroxy-3-ethyn-2-yl(2-allyl-4-ethoxycarbonylethylphenyl)- quinuclidine (lg) in dry dimethylformamide (6ml) under an atmosphere of argon to give a blue solution. Trimethylsilyl chloride (0.43ml) was added dropwise to the reaction mixture and the reaction mixture stirred for 16 hours. The reaction mixture was poured into water, extracted with ethylacetate, washed with saturated aqueous sodium bicarbonate solution, brine, dried (MgSO₄) and evaporated. The residue was purified by chromatography on silica gel (Varian bond elut silica, gel) using ethyl acetate as eluent to give the product as a clear oil (1.04g); NMR[CDCl₃] : 0.05 (9H,s), 1.0-1.1 (3H, t), 1.1-1.3 (1H, m)

1.3-1.5 (1H,m), 1.7-1.9 (3H,m), 2.3-2.45 (2H, t), 2.5-2.8 (6H,m),

2.8-2.9 (1H,d), 3.05-3.15 (1H,dd), 3.25-3.35 (2H, d), 3.85-4.0 (2H, q), 4.8-4.9 (2H,m), 5.65-5.85 (1H,m), 6.8-6.9 (2H, m) and 7.1-7.2 (1H, d); m/z (M+H) 440.

EXAMPLE 3

Concentrated hydrochloric acid (4 drops) was added to a solution of 3-trimethylsilyloxy-3-[2-(2-allylphenyl-4-ethyl- (1,2,3,4-tetrazolyl) ethynyl) quinuclidine (0.5g) dissolved in methanol (5ml) and the reaction mixture was stirred at ambient temperature for 16 hours. The reaction mixture was evaporated to dryness and the residue purified by chromatography on silica gel (Varian Bond Elut silica) using a 90:9:1 (v/v/v) mixture of ethyl

acetate/methanol/ammonia, density 0.88g/cm as eluent to give 3-[2-(2-allyl-4-(2-tetrazol-5-ylethyl)phenyl)ethynyl]quinuclidin-3-ol

(80mg) as a solid, m.p. 226.2°C, NMR [DMSOd₆ + CD₃CO₂D) : 1.7-1.9 (1H,m),

1.95-2.1 (1H,m), 2.1-2.4 (3H,d), 3.0-3.6 (12H, m), 5.0-5.1 (2H, m),

5.85-6.05 (1H,m), 7.05-7.1 (2H, m) and 7.3-7.4 (1H, d); m/z (M+H) 364.

The 3-trimethylsilyloxy-3-[2-(2-allylphenyl-

4-ethyl(1,2,3,4-tetrazolyl)ethynyl)quinuclidine was prepared in the following manner.

Imidazole (2.13g) was added to a solution of

3-[2-(2-allyl-4-(3-propionitrile)phenyl)ethynyl]quinclidin-3-ol (4g) in dimethylformamide (25ml) under an atmosphere of argon.

Trimethylsilylchloride (1.7g) was then added to the reaction mixture in a dropwise manner. The reaction mixture was stirred for 2 hours. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The ethyl acetate extract was washed with

saturated aqueous sodium bicarbonate, brine, dried (MgSO₄) and evaporated. The residue was purified by chromatography on a pad of silica gel (Merck 9385) using ethyl acetate followed by a 9:1 (v/v) mixture of ethyl acetate/methanol as eluent to give

3-trimethylsilyloxy-3-[2-(2-allyl-4-(3-propionitrile)phenyl)ethynyl- quinclidine as a pale yellow oil (4.63g); NMR[CDCl₃]: 0.15 - 0.25 (9H,s), 1.3-1.4 (1H,m), 1.5-1.7 (1H, m), 1.85-2.05 (3H, m),

2.5-2.6 (2H,t),2.7-3.1 (7H,m), 3.2-3.3 (2H, m), 3.45-3.55 (2H, d),

4.95-5.1 (2H,m), 5.85-6.05 (1H,m), 7.0-7.1 (2H,m) and 7.3-7.4 (1H, d);

microanalysis found: C,72.6; H, 8.30; N, 7.1%; C₂₄H₃₂N₂O Si 0.25 H₂O requires: C, 72.6; H, 8.2; N, 7.06%; m/z (M+H) 393.

Trimethyl silyl azide (3.14ml) and dibutyltinoxide (294mg) were added to a solution of 3-trimethylsilyloxy-3-[2-(2-allyl-4-(3- propionitrile) phenyl) ethynyl] quinclidine (4.63g) in toluene (30ml) under an atmosphere of argon. The reaction mixture was heated at reflux for 16 hours. The reaction mixture was cooled to ambient temperature and methanol (5ml) was added. The mixture was evaporated to dryness. Ethyl acetate was added to the residue and the mixture was washed with saturated aqueous sodium bicarbonate solution, dried (MgSO₄) and evaporated. The residue was purified by chromatography on a pad of silica gel (Merck 9385) using a 1:1 (v/v) mixture of ethyl acetate/methanol as eluent to give 3-trimethylsilyloxy-3-[2-(2-allyl- -4-(2-tetrazol-5-ylethyl) phenyl) ethynyl] quinuclidine as a foam

(2.15g); NMR[CDCl₃]: 0.1-0.3 (9H, s), 1.4-1.9 (2H, m), 1.9-2.3 (3H, m), 2.8-3.5 (12H,m), 4.3-5.1(2H,m), 5.6-5.95 (1H, m) and 6.9-7.4 (4H,m);

microanalysis, found C, 65.9; H, 7.4; N, 15.9%; C₂₄H₃₃N₅OSi, requires: C, 66.2; H, 7.4; N, 16.1%; m/z 436 (M+H).

EXAMPLE 4

An ice-cooled solution of aqueous 3M hydrochloric acid (5ml) in acetone (15ml) was added to

3-[2-(4-pyridylmethyl)phenoxymethyl]quinuclidin-3-ol borane complex

(1.0g). The resulting solution was stirred for 1 hour at 5°C and then evaporated at 30°C to give a slurry. The residue was dissolved in 2M hydrochloric acid (30ml). The solution was washed with ethyl acetate

(2 x 50ml), basified with solid sodium carbonate and extracted with ethyl acetate (2 x 70ml). The ethyl acetate extracts were combined, dried (Na₂SO₄) and evaporated. The residue was a colourless gum which crystallised after 2 days. Trituration with ether gave

3-[2-(4-pyridylmethyl)phenoxymethyl]quinuclidin-3-ol (0.56g) as a colourless solid, m.p 71-74°C; microanalysis, found: C, 72.3; H, 7.8;

N, 8.4%; C₂₀H₂₄N₂O₂ 0.5 H20 requires: C, 72.0; H, 7.6; N, 8.4%;

NMR(CDCl₃) : 1.2-1.4 (1H, m), 1.4-1.6 (2H, m), 1.7-1.8 (1H, m),

1.9-2.1 (1H,m), 2.1-2.4 (1H,br), 2.55-3.0 (6H, m), 3.8-4.05 (2H, q),

4.02 (2H,s), 6.85-7.35 (6H,m) and 8.45-8.55 (2H, m); m/z 325 (M+H).

The 3-[2-(4-pyridylmethyl)phenoxymethyl] quinuclidin-3-ol borane complex used as starting material was prepared as follows.

A solution of 2-bromoanisole (45.0g) in dry diethyl ether (300ml) was added dropwise over 35 minutes to a stirred suspension of magnesium turnings (5.8g) in dry diethyl ether (50ml) under an

atmosphere of argon. The reaction was initiated with an iodine

crystal and gentle heating. The solution of 2-bromoanisole was added at a rate so as to maintain the mixture at reflux temperature. A solution of 4-cyanopyridine (20.8g) in dry diethyl ether

(300ml) was added dropwise over 50 minutes to the solution of

2-methoxyphenyl magnesium bromide. The yellow mixture was stirred at ambient temperature for 16 hours. Water (25ml) was added dropwise to the mixture whilst maintaining the temperature of the mixture below 10°C. A saturated aqueous solution of ammonium chloride (300ml) was added to the mixture over 5 minutes. The aqueous phase was separated and extracted with ether (2 x 300ml). The ether solutions were combined, washed with water (2 x 300ml) and extracted with 10% aqueous methane sulphonic acid solution (4 x 150ml). The aqueous extracts were combined and treated with aqueous ammonia solution, density 0.88g/cm³ , (70ml) to give pH9. The mixture was extracted with ether (3 x 500ml). The ether extracts were combined, washed with water (500ml), dried (Na₂SO₄) and evaporated. The residue was distilled to give

4-(2-methoxybenzoyl) pyridine (23.6g) as a pale yellow oil, b.p.

130-144°C (at 0.2mmHg); microanalysis, found: C, 73.3; H,5.4; N, 6.6%; C₁₃H₁₁NO₂ requires: C, 73.2; H, 5.2; N, 6.6%; NMR (CDCl₃): 3.7(3H,s), 6.95-7.1 (2H,m), 7.4-7.6 (4H, m) and 8.7-8.8 (2H, m); m/z 214 (M+H).

Solid potassium hydroxide (14. Ig) was added to a stirred solution of 4-(2-methoxybenzoyl) pyridine (10.7g) in ethylene glycol (150ml). The mixture was heated under an atmosphere of argon to give an orange solution. Hydrazine hydrate (7.3ml) was added and the solution was heated at reflux (157°C) for 1 hour. The aqueous liqour was distilled off until the internal temperature was 196°C. The residual solution was refluxed for 2 hours.

The ethylene glycol solution was cooled to ambient temperature and extracted with dichloromethane (4 x 200ml, 4 x 100ml).

The dichloromethane extracts were combined, washed with water (4 x

60ml), dried (Na₂SO₄) and evaporated to give

4-(2-methoxybenzyl) pyridine (9.7g) as a pale yellow oil; NMR(CDCl₃):

3.8 (3H,s), 3.95(2H,s), 6.85-6.95 (2H, m), 7.05-7.15 (3H, d), 7.2-7.3 (1H,m) and 8.35-8.55 (2H,d); m/z 200 (M+H).

An aliquot was distilled (160°C at 0.08 mmHg) to give a colourless solid, m.p. 44-46°C.

Dry hydrogen chloride gas was passed into a solution of

4-(2-methoxybenzyl) pyridine (6.1g) in dry diethyl ether (100ml) until precipitation was complete. The mixture was evaporated to a white solid. Solid pyridine hydrochloride (31.9g) was added. The solids were well mixed and heated for 1.5 hours at reflux under an atmosphere of argon. Ice-water (100ml) was added to the solidified mass at

100°C. Aqueous ammonia solution, density 0.88g/cm³, (30ml) was added to the mixture to give pH8. The mixture was extracted with ethyl acetate (4 x 150ml). The ethyl acetate extracts were combined, washed with water (5 x 150ml) and extracted with 2M sodium hydroxide solution

(3 x 50ml). The alkaline aqueous extracts were combined, cooled in ice, washed with ethyl acetate and acidified with 5M hydrochloric acid

(10ml) to pH6. The mixture was extracted with ethyl acetate (4 x

150ml). The ethyl acetate extracts were combined, dried (Na₂SO₄) and evaporated to a solid. This was triturated with diethyl ether to give

4- (2-hydroxybenzyl) pyridine (4.1g) as an off-white solid, m.p.

177-180°C; microanalysis found: C, 77.5; H, 6.1; N, 7.4%; C₁₂H₁₁NO requires: C, 77.8; H, 6.0; N, 7.6%; NMR: 3.85-3.95 (2H, s),

6.7-6.9 (2H,m), 7.0-7.15 (2H, m), 7.1-7.25 (2H, d), 8.2-8,6 (2H, br) and

9.4-9.5 (1H,s); m/z 186 (M+H).

Solid potassium carbonate (2.2g) was added to a stirred solution of 4-(2-hydroxybenzyl) pyridine (1.48g) and

3-methylenequinuclidine oxide borane complex (1.22g) in dry

dimethylformamide (10ml). The mixture was heated for 3.5 hours at

75°C under an atmosphere of argon. The mixture was poured into water

(100ml) and extracted with ethyl acetate (4 x 70ml). The ethyl acetate extracts were combined, cooled in ice, washed with 2M sodium hydroxide solution (4 x 25ml) and water (4 x 70ml), dried (Na₂SO₄) and evaporated. The residual gum (2.9g) was purified by flash

chromatography on Kieselgel silica gel using a mixture of 20 - 40% ethyl acetate/dichloromethane as eluent to give

3-[2-(4-pyridylmethyl)phenoxymethyl] quinuclidin-3-ol borane complex (1.7g) as a colourless solid. An aliquot was triturated with ethyl acetate to give a solid with m.p. 156-158°C; microanalysis, found: C, 70.9; H, 8.1; N, 8.1%; C₂₀H₂₇BN₂O₂ requires: C, 71.0; H, 8.1; N, 8.3%;

NMR: 0.5-2.4 (3H,br), 1.3-1.8 (3H,m), 1.9-2.0 (1H,m), 2.0-2.2 (1H,m), 2.6-3.0 (6H,m), 3.85-4.1 (4H,m), 5.1 (1H,s), 6.85-7.1 (2H,m),

7.15-7.25 (4H,m) and 8.35-8.45 (2H,d); m/z 339 (M+H) . EXAMPLE 5

Using a similar procedure to that described in Example 1, but using 3-(4-bromo-2,6-dimethylphenoxy) tetrahydrofuran as starting material in place of pyridyl-2-methyl 3-(3-allyl-4-trifluromethyl- sulphonyloxyphenyl)propionate there was obtained 3-[2-(4-[tetrahydrofuran-3-yloxy]-3,5-dimethylphenyl)ethynyl]quinuclidin-3-ol (23% yield) as a solid , m.p. 163-164°C (after recrystallisation from

acetonitrile); microanalysis, found: C, 73.8; H, 8.1, N, 4.2%;

C₂₁H₂₇NO₃ requires: C, 73.9; H, 8.0; N, 4.1%; NMR: 1.2-1.4 (1H,m), 1.5-1.65 (1H,m), 1.7-2.0 (3H,m), 2.0-2.1 (2H,m) , 2.2 (6H,s),

2.6-2.75 (4H,t), 2.75-2.9 (1H, d) , 2.95-3.1 (1H, d) , 3.6-4.0 (4H, m),

4.7-4.8 (1H,m), 5.5 (1H,s) and 7.1 (2H,s); m/z 342 (M+H).

The 3-(4-bromo-2,6-dimethylphenoxy) tetrahydrofuran used as a starting material was obtained as follows.

A solution of diethylazodicarboxylate (2.61g) in tetrahydrofuran (5ml) was added portionwise over a period of 30 minutes to a stirred solution of triphenylphosphine,

4-bromo-2,6-dimethylphenol (3.01g) and 3-hydroxytetrahydrofuran

(1.32g) in dry tetrahydrofuran (20ml) under an atmosphere of argon at 0°C. The resultant mixture was allowed to attain ambient temperature and stirred for a further 18 hours. The tetrahydrofuran was removed by evaporation and the residue dissolved in diethyl ether (100ml), washed with 2N aqueous sodium hydroxide (6 x 20ml), water (20ml), dried (MgSO₄) and evaporated. The residue was purified by flash column chromatography on silica gel (Merck Art No 9385) using 5% ethyl acetate/hexane as eluent to give

3-(4-bromo-2,6-dimethylphenoxy)tetrahydrofuran (1.9g) as an oil;

NHR(CDCl₃) : 2.0-2.20 (2H,m), 2.25 (6H,s), 3.67-3.74 (1H, d of d),

3.86-3.96 (2H,m), 4.04-4.16 (1H, d of d), 4.6-4.7 (1H,m) and 7.14 (2H, s).

EXAMPLE 6

Using a similar procedure to that described in Example 1 but using N-(2-(4-bromophenoxy)ethyl)succinimide as starting material in place of pyridyl-2-methyl 3-(3-allyl-4-trifluoromethylsulphonyloxy- phenyl)propionate and extracting the aqueous mixture obtained after diluting the reaction mixture with 2M aqueous sodium hydroxide with dichloromethane instead of ethyl acetate, there was obtained

3-[2-(4-(2-N-succinimido) ethoxy) phenyl) ethynyl) quinuclidin-3-ol (34% yield) as a solid, m.p. 188-189°C (after recrystallisation from acetonitrile); microanalysis, found C, 68.0; H, 6.5; N, 7.6%;

C₂₁H₂₄N₂O requires: C, 68.5; H, 6.6; H, 7.6%; NMR: 1.2-1.4 (1H,m),

1.5-1.7 (1H,m), 1.8-2.0 (3H,m), 2.6-2.65 (4H,s), 2.65-2.75 (4H,m),

2.75-2.9 (1H,d), 3.0-3.15 (1H,d), 3.7-3.8 (2H, t), 4.1-4.2 (2H, t),

5.5 (1H,S), 6.8-6.9 (2H,d), 7.3-7.4 (2H,d); m/z 369 (M+H).

The N-(2-(4-bromophenoxy) ethyl succinimide used as a starting material was obtained in a similar manner to that for the preparation of 3-(4-bromo-2,6-dimethylphenoxy)tetrahydrofuran described in Example 5, but using 2-(4-bromophenoxy)ethanol and succinimide as starting materials.

EXAMPLE 7

Using a similar procedure to that described in Example 1 but using 1-(4-bromophenoxy-2-pyrid-3-yloxyethane as starting material in place of 1-(4-bromo-2,6-dimethylphenoxy)-2-methoxyethane, there was obtained 3-[2-(4-{2-pyrid-3-yloxyethoxy}phenyl)ethynylquinuclidin-3-ol (29% yield) as a solid, m.p. 155-157°C (after recrystallisation from acetonitrile); microanalysis, found C, 72.3; H, 6.6, N, 7.6%;

C₂₂H₂₄N₂O₃ requires: C, 72.5; H, 6.6; N, 7.7%; NMR: 1.2-1.4 (1H, m),

1:5-1.7 (1H,m), 1.75-2.0 (3H,m), 2.6-2.75 (4H, t), 2.75-2.9 (1H, d),

2.95-3.1 (1H,d), 4.25-4.45 (4H,q), 5.5 (1H,s), 6.9-7.0 (2H, d),

7.25-7.5 (4H,m), 8.1-8.2 (1H,d of d) and 8.3-8.4 (1H, d); m/z 365 (M+H).

The 1-(4-bromophenoxy)-2-pyrid-3-yloxyethane (m.p. 94-95°C) used as a starting material was obtained using a similar procedure to that for the preparation of

3-(4-bromo-2,6-dimethylphenoxy)tetrahydrofuran in Example 5 but starting from 3-hydroxypyridine and 2-(4-brorophenoxy)ethanol. EXAMPLE 8

The procedure described in Example 1 was repeated using 3- (4 -bromobenzoyl) pyridine as starting material in place of

pyridyl-2-methyl 3-(3-allyl-4-trifluoromethylsulphonyloxyphenyl)propionate. There was thus obtained, after purification by chromatography on silica gel using a mixture of 10% methanol in dichloromethane containing 1% ammonia (density, 0.88g/cm³) as eluent and recrystallisation from acetonitrile, 3-[2-(4-(pyrid-3-ylcarbonyl) phenyl) ethynyllquinuclidin-3-ol, as a solid, m.p. 219-220°C;

(microanalysis, found: C, 74.9; H, 6.0; N, 8.3%; C₂₁H₂₀N₂O₂ requires: C, 74.7; H, 6.15; N, 8.29%; NMR: 1.25-1.4 (1H,m), 1.55-1.7 (1H,m), 1.8-2.05 (3H,m) , 2.55-2.70 (4H, m), 2.85 (1H,d), 3.15 (1H,d), 5.75 (1H,s), 7.55-7.65 (3H,m), 7.8 (2H,d), 8.1 (1H,m), 8.8-8.9 (2H,m); m/z 333 (M+H).

EXAMPLE 9

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:-

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 3

ion

SPHERE

Claims

CLAIMS 1. A compound of formula I,

or a pharmaceutically acceptable salt thereof, wherein:

R¹ is hydrogen or hydroxy;

R² is hydrogen; or

R¹ and R² are joined together so that CR¹-CR² is a double bond;

X is selected from -CH2CH2-, -CH=CH-, -C≡C-, -CH₂O-, -CH₂NH- ,

-NHCH₂, -CH₂CO-, -COCH₂-, -CH₂S(O)_n- and -S (O) _nCH₂- (wherein n is 0,1 or 2);

Ar is phenyl which bears one or more substituents independently selected from the groups (1-6C) alkyl, (2 -6C) alkenyl, (2-6C) alkynyl, (1-6C)alkoxy, (1-6C) alkoxycarbonyl,

(1-6C) alkoxycarbonyl (1-6C) alkyl, (1-6C) alkoxy(1-6C) alkyl,

(1-6C) alkylamino, di- [ (1-6C) alkyl] amino, carbamoyl,

(1-6C) alkylcarbamoyl, di-[(1-6C) alkyl] carbamoyl,

(1-6C) alkanoyl and oxime derivatives thereof and 0-(1-6C) alkyl ethers of said oximes, (1-6C) alkylthio, (1-6C) alkylsulphinyl and

and wherein Ar and/or a phenyl or heterocyclyl moiety in any of said groups mentioned above 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, (1-6C) alkanoylamino,

(1-4C) alkylenedioxy, (1-6C) alkanoyl and oxime derivatives thereof and

0- (1-6C) alkyl ethers of said oxime derivatives; provided that when X is -OCH₂-, -NHCH₂- or -S (O)_nCH₂ - (wherein n is 0,1 or 2), then R¹ is not hydroxy; and provided that when R¹ andR² are not both hydrogen or joined together, then X is not -OCH₂-.

2. A compound as claimed in claim 1 or 2 wherein R¹ is hydroxy and R² is hydrogen.

3. A compound as claimed in claim 1 or 2 wherein X is selected from -CH₂CH₂-, -CH=CH-, -C≡C- and -CH₂O-.

4. A compound as claimed in claim 1 or 2 wherein X is -C≡C-.

5. A compound as claimed in claim 1, 2, 3 or 4 wherein the heterocyclyl moiety is selected from furyl, pyrrolyl, thienyl, pyridyl, pyrimidinyl, pyridazinyl, imidazolyl,

oxazolyl, isooxazolyl, thiazolyl, isothiazolyl, oxadiazolyl,

tetrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, benzfuranyl, quinolyl, isoquinolyl, benzimidazolyl, indolyl, benzthiazolyl, benzodioxolyl, benzodioxanyl and benzodihydrofuranyl; and partially or fully

hydrogenated derivatives thereof.

6. A compound as claimed in claim 5 wherein Ar is phenyl which bears one or more substituents independently selected from

heterocyclyloxy, heterocyclyl (1-6C) alkyl, heterocyclyloxy (1-6C) alkoxy, heterocyclyl (1-6C) alkoxycarbonyl, heterocyclylcarbonyl; and, in addition, optionally bears 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 (1-6C) alkyl] amino

N-(1-6C) alkylcarbamoyl, di-N,N-1 (1-6C)alkyl]carbamoyl,

(1-6C) alkoxycarbonyl, (1-6C) alkylthio, (1-6C) alkylsulphinyl,

(1-6C) alkylsulphonyl, halogeno (1-6C) alkyl, (1-6C) alkanoylamino, (1-4C) alkylenedioxy, (1-6C) alkanoyl and oxime derivatives thereof and 0-(1-6C) alkyl ethers of said oxime derivatives.

7. A compound as claimed in claim 6 wherein Ar is phenyl which bears one or two substituents selected from pyridyl (1-6C) alkoxycarbonyl, tetrazolyl (1-6C) alkyl, oxadiazolyl (1-6C) alkyl,

pyridyl (1-6C) alkyl, tetrahydrofuranyloxy, N-succinimido (1-6C) alkoxy, pyridyloxy (1-6C) alkoxy and pyridylcarbonyl; and optionally one or two substituents selected from (1-6C) alkyl, (2-6C) alkenyl, halogeno, (1-6C) alkoxy and (1-6C) alkanoyl.

8. A compound as claimed in claim 1 wherein R¹ is hydroxy, R² is hydrogen, X is -C≡C- and Ar is phenyl which bears one or two substituents selected from pyridyl (1-6C) alkoxycarbonyl,

tetrazolyl (1-6C) alkyl, oxadiazolyl (1-6C) alkyl, pyridyl (1-6C) alkyl, tetrahydrofuranyloxy, N-succinimido (1-6C) alkoxy,

pyridyloxy (1-6C) alkoxy and pyridylcarbonyl; and optionally one or two substituents selected from (1-6C) alkyl, (2 -6C) alkenyl, halogeno,

(1-6C) alkoxy and (1-6C) alkanoyl.

9. A process for preparing a compound of formula I, or a pharmaceutically acceptable salt thereof, as claimed in claim 1 which process is selected from:

(a) for those compounds of formula I in which R¹ and R² are both hydrogen, reducing a compound of formula I in which R¹ and R² are .joined together so that CR¹-CR² is a double bond;

(b) for compounds of formula I in which R¹ and R² are joined together so that CR¹-CR² is a double bond, dehydrating a compound of formula I in which R¹ is hydroxy and R² is hydrogen;

(c) for compounds of formula I in which R¹ and R² are joined together so that CR¹-CR² is a double bond, treating a compound of formula II:

in which Z is a leaving group with a base;

(d) for those compounds of formula I in which X is -CH₂CO-, reacting an organometallic compound of formula III:

Ar-M

(III)

in which M is a metal atom or a derivative thereof, with a compound of formula IV;

)

(e) for those compounds of formula I in which X is -CH NH- or

-NHCH₂-, reducing a compound of formula I in which X is -CH=N- or -N=CH- ( as appropriate);

(f) for those compounds of formula I in which X is -CH₂NH- , -CH₂O- or -CH₂S-, R1 is hydroxy and R2 is hydrogen, reacting a compound of formula IX in which Z is -NH₂, -OH or SH as appropriate with a compound of formula X: ( IX )

Ar-Z

(g) for compounds of formula I in which X is -CH=CH-, reacting a compound of formula XI:

)

with a compound of formula V in the presence of a base;

(h) for those compounds of formula I in which X is -CH₂CH₂- reducing a compound of formula I in which X is -CH=CH-;

(i) for compounds of formula I in which X is -COCH2-, reacting a compound of formula XII:

Ar-CH₂M (XII)

in which M is a metal atom or a derivative thereof, with a compound of formula XIII:

(j ) for those compounds of formula I in which X is -CH₂O- or

-CH2S-, reacting a compound of formula XIV:

ArCH₂Z¹ (XIV)

with a compound of formula XV:

in which Z¹ is a leaving group and Z² is -YM, or Z¹ is -YM and Z² is a leaving group, and wherein Y is oxygen or sulphur (as

appropriate) and M is a metal atom;

(k) for those compounds of formula I in which X is -OCH₂- or -SCH₂- and R¹ and R² are both hydrogen, reacting a compound of formula

XVI: ArYH

(XVI)

in which Y is oxygen or sulphur as appropriate with a compound of formula XVII:

in which Z is a leaving group;

(1) for compounds of formula I in which X is -OCH₂ -SCH₂-,

-CH₂O-, or -CH₂S-, deprotecting a compound of formula XVIII in which Q

is a protecting group;

(m) for those compounds of formula I in which X is -C≡C-, reacting a compound of formula I in which X is -CH=CH- with a halogen, followed by treatment with a base;

(n) for those compounds of formula I in which R¹ is hydroxy, R² is hydrogen and X is -C≡C-, reacting a compound of formula XIX: Ar-C≡CM

(XIX)

in which M is a metal atom, with quinuclidin-3-one;

(o) for those compounds in which R¹ and R² are hydrogen and X is

-C≡C-, reacting a compound of formula XIX in which M is a metal atom with a compound of formula XV:

in which Z is a leaving group;

(p) for those compounds in which X is -C≡C- and R¹ is hydrogen or hydroxy and R² is hydrogen, reacting a compound of formula XX:

with a compound of formula IX in which Z is a leaving group in the

Ar-Z (IX) presence of a catalyst; (q) for those compounds in which X is -C=C- and R1 is hydrogen or hydroxy and R² is hydrogen, reacting a compound of formula XXI:

with a compound of formula IX in which Z is a leaving group in the

Ar-Z (IX) presence of a catalyst;

and whereafter, when a pharmaceutically acceptable salt is required treating the compound of formula I with an acid which affords a pharmaceutically acceptable anion or a base which affords a

pharmaceutically acceptable cation.

10. A pharmaceutical composition comprising a compound of formula I as claimed in claim 1 together with, or in admixture with, a pharmaceutically acceptable diluent or carrier.

11. The use of a compound of formula I, or a pharmaceutically acceptable salt thereof, as defined in claim l, for the manufacture of a medicament for treating diseases or medical conditions in which a lowering of cholesterol in blood plasma is desirable.