WO1992005148A1

WO1992005148A1 - Imidazol derivatives, process for their preparation and their applications

Info

Publication number: WO1992005148A1
Application number: PCT/GB1991/001651
Authority: WO
Inventors: Andrew William Bridge; Neil Victor Harris; David John Lythgoe; Christopher Smith
Original assignee: Rhone Poulenc Rorer Ltd
Current assignee: Rhone Poulenc Rorer Ltd
Priority date: 1990-09-25
Filing date: 1991-09-25
Publication date: 1992-04-02
Anticipated expiration: 1993-03-25
Also published as: JPH06501463A; CA2092309A1; AU8544091A; GB9020889D0

Abstract

Imidazole derivatives of the formula (I): [DPIM]-X-Z-Y wherein [DPIM] is a 4,5-diphenylimidazol-2-yl grouping in which the phenyl groups are optionally substituted by halogen, alkyl or alkoxy, X represents a direct bond or alkylene, alkenylene or alkynylene of up to 3 carbon atoms, Z represents a direct bond or, when X is other than a direct bond, Z represents oxygen, -O-CH2- or -NH-, and Y represents alkoxycarbonyl, optionally substituted alkyl, optionally substituted phenyl or heterocyclyl, or a group of formula (II), (III), (IV), wherein m is 2, 3 or 4, p is 0, 1, 2, 3, 4 or 5, q is 0 or 1, r is 1, 2, 3 or 4, provided that formulae (III) and (IV) each represents a 5-, 6- or 7-membered ring, and Q represents optionally substituted methylene, and pharmaceutically acceptable salts thereof possess useful pharmacological properties.

Description

IMIDAZOL DERIVATIVES,

PROCESS FOR THEIR PREPARATION AND THEIR APPLICATIONS

This invention relates to therapeutically useful imidazole derivatives, to a process for their

production, to pharmaceutical compositions containing them, and to their use in a method of treatment of the human or animal body.

Accordingly, this invention provides imidazole derivatives of the present invention are the compounds of the general formula:-

[DPIM]-X-Z-Y I

wherein [DPIM] is as hereinafter depicted, the symbols R¹ are the same or different and each represents a halogen atom or an alkyl or alkoxy group containing from 1 to about 3 carbon atoms, the symbols n are the same or different and each represents 0 or an integer from 1 to about 5, X represents a direct bond or an alkylene, alkenylene or alkynylene group containing up to about 3 carbon atoms, Z represents a direct bond or, when X is other than a direct bond, Z represents an oxygen atom, a group of formula -O-CH₂- or -NH-, and Y represents an alkoxycarbonyl group containing up to about 5 carbon atoms, an alkyl group of up to about 3 carbon atoms optionally substituted, for example by one or more alkoxy groups each containing up to about 3 carbon atoms, an optionally substituted phenyl or heterocyclyl, e.g. pyridyl, group, or a group of the general formula II, III or IV hereinafter depicted, wherein m represents 2, 3 or 4, the symbols p are the same or different and each represents 0, 1, 2, 3, 4 or 5, q represents 0 or 1, the symbols r are the same or different and each represents 1, 2, 3 or 4, provided that p, q and r are such that formulae III and IV each represents a 5-, 6- or 7-membered ring, and the symbols Q are the same or different and each represents a methylene group optionally substituted by one or two substituents selected from alkoxy groups of 1 to about 5 carbon atoms and from alkyl groups of 1 to about 5 carbon atoms optionally substituted by one or more substituents selected from, for example, halogen atoms, hydroxy groups, acyloxy groups, alkoxy groups of 1 to about 5 carbon atoms (which themselves may each be substituted, for example, by a hydroxy or acyloxy group, or by a heterocyclyl, e.g. pyrazolyl,

morpholinyl or piperidinyl, group which itself is optionally substituted by one or more substituents selected from alkyl groups containing up to 3 carbon atoms and optionally substituted phenyl groups), and phenyl groups (which themselves are optionally

substituted by one or more substituents selected from halogen atoms and alkyl and alkoxy groups each

containing up to 3 carbon atoms), or Q represents a methylene group substituted by each end of an alkylene chain (of up to about 8 carbon atoms, optionally interrupted by one or more double bonds and/or by one or more heteroatoms, e.g. nitrogen, sulphur or oxygen atoms and optionally substituted by one or more alkyl groups of 1 to about 5 carbon atoms optionally substituted by one or more substituents selected from, for example, hydroxy groups, alkoxy groups of 1 to about 5 carbon atoms, amino groups, alkylamino groups of 1 to about 5 carbon atoms, and dialkylamino groups of 1 to about 5 carbon atoms in each alkyl moiety) to form a ring; and pharmaceutically acceptable salts thereof; with the proviso that, when X represents a direct bond, R¹ is alkoxy, or Y is other than a 1,3-dicxocycloalk- 2-yl group optionally substituted by one or more alkyl groups each of 1 to 3 carbon atoms and with the proviso that, when X represents a direct bond, Y is other than a 1,3-dioxan-2-yl group substituted on the 5-position by one or more alkyl groups containing from 1 to 3 carbon atoms substituted by one or more halogen atoms, by a hydroxy or acyloxy group, by an alkoxy group containing from 1 to 3 carbon atoms which itself is optionally substituted by a hydroxy or acyloxy group, or by a phenyl group which itself is optionally

containing up to 3 carbon atoms, and Y is other than a 1,3-dioxan-2-yl group substituted on the 5-position by an alkylene or alkenylene chain which together with the carbon atom to which it is attached forms a cycloalkane or cycloalkene group containing from 5 to 7 carbon atoms;

and pharmaceutically acceptable salts thereof.

In the above definition of Q the term "acyloxy" preferably represents an alkanoyloxy group containing up to about 6 carbon atoms or a benzoyloxy group.

Especially important features of the present invention are, or involve, compounds of general formula I wherein at least one of the symbols has a value selected from the following:-

(i) n represents 0;

(ii) Z represents a direct bond;

(iii) Y represents an alkoxycarbonyl, preferably ethoxycarbonyl group, or a substituted or, preferably, unsubstituted, phenyl or heterocyclyl, preferably pyridyl, group, or a group of the general formula II, III or IV;

(iv) m represents 2 or 3;

(v) p represents 0 or 4; and

(vi) Q represents a methylene group optionally substituted by one or two substituents selected from alkyl, preferably methyl, groups [optionally

substituted by one or two substituents selected from hydroxy groups, and from alkoxy, preferably ethoxy, groups (which themselves may be substituted by a heterocyclyl, e.g. pyrazolyl, morpholinyl or

piperidinyl, group which itself is optionally

substituted by one or more substituents selected from alkyl, e.g. methyl, groups and substituted and, preferably, unsubstituted phenyl groups)]; or Q

represents a methylene group substituted by each end of a 1,2-ethylenedioxy chain;

the other symbols being as hereinbefore defined, and pharmaceutically acceptable salts thereof.

Preferred salts are acid addition salts such as the hydrochlorides.

Important compounds according to the invention include:-:

A (E)-4,5-diphenyl-2-(2-phenylethenyl)imidazole; B (E)-4,5-diphenyl-2-[2-(3-pyridyl)ethenyl]- imidazole;

C 2-(3-pyridyl)-4,5-diphenylimidazole;

D 2-phenylethynyl-4,5-diphenylimidazole;

E (E)-2-[2-(ethoxycarbonyl)ethenyl]-4,5-diphenyl- imidazole;

F (E)-2-[2-(dioxolan-2-yl)ethenyl]-4,5-diphenyl- imidazole; G (E)-2-[2-(5,5-dimethyl-1,3-dioxan-2-yl)ethenyl]-

4,5-diphenylimidazole;

H (E)-2-[3-(1,3-dioxan-2-yl)propen-1-yl]-4,5- diphenylimidazole;

I 2-[2-(dioxolan-2-yl)ethyl]-4,5-diphenyl- imidazole;

J 2-[2-(5,5-dimethyl-1,3-dioxan-2-yl)ethyl]-4,5- diphenylimidazole;

K 2-[2-(1,3-dioxan-2-yl)ethyl]-4,5-diphenyl- imidazole;

L 2-[2-(4,5-dimethyldioxolan-2-yl)ethyl]-4,5- diphenylimidazole;

M 2-[3-(1,3-dioxan-2-yl)propyl]-4,5-diphenyl- imidazole;

N 4-(4,5-diphenylimidazol-2-yl)-2H-5,6-dihydro- pyran;

O 1-(4,5-diphenylimidazol-2-yl)-4,4-dimethyl- cyclohexene;

P 1-(4,5-diphenylimidazol-2-yl)cyclohexene;

Q 8-(4,5-diphenylimidazol-2-yl)-1,4-dioxaspiro-

[4,5]dec-7-ene;

R 1-(4,5-diphenylimidazol-2-yl)-4,4-dimethylcyclo- hexane;

S [R,S]-4,5-diphenyl-2-(tetrahydropyran-2-yl)- imidazole;

T r-2-(4,5-diphenyl-2-imidazolyl)-5-methyl- t-5-[{2-(5-methyl-3-phenyl-l-pyrazolyl)- ethoxy}methyl]-1,3-dioxane;

U r-2-(4,5-diphenyl-2-imidazolyl)-5-methyl- c-5-[{2-(5-methyl-3-phenyl-1-pyrazolyl)- ethoxy}methyl]-1,3-dioxane;

V r-2-(4,5-diphenyl-2-imidazolyl)-5-methyl-c-5- [{2-(1-piperidinyl)ethoxy}methyl]-1,3-dioxane; W 2-(4,5-diphenyl-2-imidazolyl)-5-(hydroxymethyl)- 5-[{2-(4-morpholinyl)ethoxy}methyl]-1,3-dioxane; and

X c-5-[(2-(3,5-dimethyl-1-pyrazolyl)ethoxy)- methyl]-r-2-(4,5-diphenyl-2-imidazolyl)-5- methyl-1,3-dioxane.

The letters A to X are allocated to compounds for easy reference later in this specification.

The compounds according to the invention are inhibitors of acyl coenzyme-A:cholesterol-O-acyl transferase (ACAT; EC 2.3.1.26). They are therefore of value as anti-atherosclerotic agents and have utility in the treatment of atherosclerosis,

hyperlipidaemia, cholesterol ester storage disease and atheroma in vein grafts, and in the reduction of the atherosclerotic plaque. They are also inhibitors of the binding of thromboxane TxA₂ to its receptors. They are

therefore of utility in the treatment of conditions such as thrombosis and myocardial infarction,

vasospastic disorders, for example associated with angina, and bronchospasm, for example associated with asthma, or in reperfusion salvage therapy, for example after ischaemic injury.

Compounds within the scope of the present invention exhibit positive pharmacological activities as demonstrated by the following in-vitro and in-vivo tests which are believed to correlate to

pharmacological activity in humans and other animals.

In in-vitro tests on human platelet membrane, compounds of the invention produced up to 50%

inhibition of the binding of thromboxane TxA₂ to its receptors at concentrations down to about 600

nanomolar or less.

In assays performed in-vitro, microsomes, obtained from the livers of rats fed on a diet

supplemented with 0.5%w/w cholesterol and 0.25%w/w cholic acid for 7 days, were incubated with

radiolabelled oleoyl-CoA in the presence of compounds according to the invention at a concentration of 0.5 or 1 μg/ml. The degree of ACAT inhibition produced was up to 95% or more. In in-vivo tests, using rats fed on a similar diet to that above and further supplemented by 0.03% w/w of test compound, the compounds according to the invention inhibited increases in plasma cholesterol concentrations, measured after 3 days, relative to control animals fed on the cholesterol supplemented diet without the drug, by up to 75% or more.

The present invention also provides a method for the treatment of a human or animal patient suffering from, or subject to, conditions which can be

ameliorated by the administration of an inhibitor of acyl coenzyme-A:cholesterol-O-acyl transferase, such as atherosclerosis, hyperlipidaemia, cholesterol ester storage disease and atheroma in vein grafts, (for example by reduction of the atherosclerotic plaque), or of an inhibitor of the binding of thromboxane TxA₂ to its receptors, such as thrombosis and myocardial infarction, vasospastic disorders, for example

associated with angina, and bronchospasm, for example associated with asthma, or in reperfusion salvage therapy, for example after ischaemic injury, which comprises administering to the patient an effective amount of a compound of formula I, or a

pharmaceutically acceptable salt thereof, as

hereinbefore defined, to secure an improvement in the condition of the patient. This invention also provides a compound of formula I, or a pharmaceutically acceptable salt thereof, as hereinbefore defined, for use in a new method of treatment, of the human or animal body, by therapy, of conditions which can be ameliorated by the administration of an inhibitor of acyl coenzyme- A:cholesterol-O-acyl transferase, such as

atherosclerosis, hyperlipidaemia, cholesterol ester storage disease and atheroma in vein grafts, (for example by reduction of the atherosclerotic plaque), or of an inhibitor of the binding of thromboxane TxA₂ to its receptors, such as thrombosis and myocardial infarction, vasospastic disorders, for example

associated with angina, and bronchospasm, for example associated with asthma, or in reperfusion salvage therapy, for example after ischaemic injury.

Compounds of formula I can be prepared by the application or adaptation of known methods, for example methods illustrated in the following Examples and

Reference Examples.

As a feature of the present invention, compounds of formula I are prepared from compounds of the general formula V hereinafter depicted, wherein R¹, n, X, Z, and Y are as hereinbefore defined and R² represents a protecting group, for example a trialkylsilylalkoxy- methyl, e.g. trimethylsilylethoxymethyl, group or a substituted or unsubstituted benzyl group, by the application or adaptation of known methods for the replacement of such a protecting group by a hydrogen atom.

For example, when R² represents a trialkylsilylalkoxymethyl group, it may be converted to a hydrogen atom by reaction with a tetraalkylammonium fluoride, e.g. tetrabutylammonium fluoride, preferably in a solvent such as tetrahydrofuran and preferably at an elevated temperature, e.g. the reflux temperature of the reaction mixture.

When R² represents a substituted or unsubstituted benzyl group, it may be converted to a hydrogen atom by reduction, for example by reaction with a mixture of sodium and ammonia, optionally in a solvent such as tetrahydrofuran. Alternatively the reduction may be carried out by catalytic hydrogenation, using a catalyst such as palladium on carbon.

According to a further feature of the invention, compounds of formula I wherein X represents a vinylene or ethynylene group, Z represents a direct bond and Y represents an optionally substituted phenyl or

heterocyclyl group, [DPIM], R¹ and n being as

hereinbefore defined, are prepared by the reaction of a compound of the general formula VI, hereinafter

depicted, wherein R¹ and n are as hereinbefore defined, with a compound of the general formula:-

Y¹-X¹-CHO VII

wherein X¹ represents a vinylene or ethynylene group and Y¹ represents an optionally substituted phenyl or heterocyclyl group, and a source of ammonia such as ammonium acetate, preferably in the presence of an acid such as acetic acid, preferably at an elevated

temperature.

According to a further feature of the invention, compounds of formula I wherein Y represents a group of formula IV, X and Z each represents a direct bond, and [DPIM], R¹, n, X, Z, Q, q and r are as hereinbefore defined, are prepared by the dehydration of compounds of general formula VIII, hereinafter depicted, wherein [DPIM], Q, q and r are as hereinafter defined. The dehydration is preferably carried out by reaction with an acid anhydride such as trifluoroacetic anhydride.

According to a further feature of the present invention, compounds of formula I wherein X and Z each represents a direct bond, Y represents a group of formula III as hereinbefore defined wherein q

represents 0, p+p equals 3, 4, 5 or 6, and Q and [DPIM] are as hereinbefore defined, are prepared by the reduction, e.g. the catalytic hydrogenation, of

compounds of general formula IX, hereinafter depicted, wherein p¹ represents 2, 3, 4 or 5, R³ represents a hydrogen atom or, preferably, a protecting group, for example a substituted or unsubstituted benzyl group, and R¹, n and Q are as hereinbefore defined.

Palladium on carbon is generally a suitable catalyst for this reaction.

Compounds of formulae V, VI, VII, VIII and IX can be prepared by the application or adaptation of known methods, for example methods illustrated in the following Examples and Reference Examples.

It is to be understood that, where in this specification reference is made to compounds of formula I, it is intended to refer also where the context so permits to their pharmaceutically acceptable salts.

Such salts are prepared from the parent compounds of formula I by the application or adaptation of known methods, or are produced by the processes described herein. Parent compounds of formula I can be

generated therefrom by the application or adaptation of known methods.

For example, acid addition salts are prepared by the reaction of the parent compound with the

appropriate acid, and the parent compounds are

regenerated therefrom by reaction with an alkali metal carbonate, bicarbonate or hydroxide in aqueous

conditions.

By the term "known methods" is meant methods known heretofore or described in the literature.

Compounds of formula I can be purified by the usual physical means, for example by crystallisation or chromatography.

The person skilled in the art will appreciate that some of the compounds of formula I can exist in more than one enantiomeric form. All such forms, their mixtures, their preparation and their use are within the scope of the present invention.

The enantiomers can be separated from their mixtures by the usual methods, e.g. chromatography, and alternatively they can be prepared from the appropriate enantiomeric forms of their intermediates.

The following Examples illustrate the

preparation of compounds according to the invention and the Reference Examples illustrate the preparation of intermediates.

In the presentation of the nuclear magnetic resonance ("NMR") spectra chemical shifts were

expressed in parts per million relative to

tetramethylsilane. Abbreviations have the following significances:- s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, dd = doublet of doublets and dt = doublet of triplets.

EXAMPLE 1

Compounds A, B, C and D

A mixture of benzil (10.5g), ammonium acetate (30.8g), and trans-cinnamaldehyde (8.8g) in acetic acid (250ml) was stirred at reflux for 2.5 hours. After cooling to room temperature, the mixture was poured into water (2000ml) and brought to pH 9 by treatment with concentrated aqueous ammonia solution . The mixture was extracted with dichloromethane (500ml), and this solution was dried over magnesium sulphate and evaporated. The resulting black oil (20g) was subjected to flash chromatography, eluting with ethyl acetate to give of an orange solid (4.5g). Crystallisation from ethyl acetate gave (E)-4,5-diphenyl-2-(2- phenylethenyl) imidazole (2.2g), in the form of a cream solid, m.p. 222-224°C. [Elemental analysis:- C,75.3; H,5.66;N,9.0%; Calculated:- C,75.45;H,5.70;N,8.80%;

NMR (CDCl₃) 6.98 (1H,d,J=16Hz), 7.2-7.6 (16H)].

By proceeding in a similar manner, but replacing the trans-cinammaldehyde by the appropriate quantity of trans-3-pyridylacrylaldehyde, there was obtained

(E)-4,5-diphenyl-2-[2-(3-pyridyl) ethenyl] imidazole, m.p. 214-217°C. [Elemental analysis:- C,81.9;H,5.2; N,12.8%; Calculated:- C,81.71;H,5.3;N,12.99%] .

By proceeding in a similar manner, but replacing the trans-cinammaldehyde by the appropriate quantity of 3-pyridinecarboxaldehyde and crystallising from aqueous ethanol, there was prepared 2-(3-pyridyl)-4,5-diphenyl- imidazole in the form of off-white needles,

m.p. 191-193°C. [Elemental analysis:- C,80.8;H,4.86; N,14.1%; Calculated:- C,80.78;H,5.08;N,14.14%].

By proceeding in a similar manner, but replacing the trans-cinammaldehyde by the appropriate quantity of phenylpropiolaldehyde diethyl acetal and crystallising from a mixture of light petroleum (b.p.40-60°C) and ethyl acetate, there was prepared 2-phenylethynyl-4,5- diphenylimidazole in the form.of a cream coloured solid, m.p. 206-208°C. [Elemental analysis:- C,84.9; H,5.03;N,8.3%; Calculated:- C,86.22;H,5.03;8.75%]. EXAMPLE 2

Compound E

A mixture of (E)-4,5-diphenyl-2-[2-(ethoxycarbonyl)ethenyl]-1-[2-(trimethylsilyl)ethoxymethyl]- imidazole (20.5g) and tetrabutylammonium fluoride (1.0M solution in tetrahydrofuran; 170ml) in anhydrous tetrahydrofuran (400ml) was stirred at reflux for 3 hours. After standing at room temperature overnight the dark mixture was evaporated to low bulk and the residue was dissolved in ethyl acetate (250ml). This solution was washed with water (3x150ml), dried over magnesium sulphate and evaporated. The residue was subjected to flash chromatography, eluting with a mixture of ethyl acetate and pentane (1:3 v/v) to give (E)-2-[2-(ethoxycarbonyl)ethenyl]-4,5-diphenylimidazole (10.2g) in the form of a pale green solid,

m.p. 198-201°C. [Elemental analysis:- C,75.5;H,5.7;

N,8.7%; Calculated:- C,75.45;H,5.70;N,8.80%;

NMR (CD₃SOCD₃):- 1.18 (3H,t,J=8Hz), 4.21 (2H,q,J=8Hz),

6.74 (1H,d,J=16Hz), 7.3-7.5 (11H,m)].

EXAMPLE 3

Compounds F and G

A mixture of 1-[2-(trimethylsilyl)ethoxymethyl]-

4, 5-diphenyl-2-(2-formylethenyl)imidazole (1.0g), ethylene glycol (2.0g), and pyridinium

4-toluenesulphonate (0.1g) in toluene (50ml) was stirred at reflux under a Dean and Stark water trap for 1 hour. After cooling to room temperature the mixture was diluted with ethyl acetate (50ml), washed with water (4x25ml), dried over magnesium sulphate and evaporated to give a pale orange gum. A solution of this gum and tetrabutylammonium fluoride (1.0M solution in tetrahydrofuran; 15ml) in anhydrous tetrahydrofuran (25ml) was stirred at reflux for 2 hours. The dark mixture was evaporated to low bulk and partitioned between ethyl acetate (75ml) and water (50ml) . The layers were separated and the ethyl acetate layer was washed with water (2x50ml), dried over magnesium sulphate and evaporated. Crystallisation of the pale brown residue from ethyl acetate gave

(E)-2-[2-(dioxolan-2-yl)ethenyl]-4,5-diphenylimidazoIe (0.44g), in the form of a white crystalline solid, m.p. 229-30°C. [Elemental analysis:- C,75.3;H,5.66;N,9.0%; Calculated:- C,75.45;H,5.70;N,8.80%; NMR (CDCl₃):- 4.00 (4H,m), 5.51 (1H,d,J=6Hz), 6.50 (1H,dd,J=6Hz, 16Hz), 6.78 (1H,d,J=16Hz), 7.20-7.60 (10H,2m)].

By proceeding in a similar manner, but replacing the ethylene glycol by the appropriate quantity of 2,2-dimethylpropane-1,3-diol, .there was prepared

(E)-2-[2-(5,5-dimethyl-1,3-dioxan-2-yl)ethenyl]-4,5- diphenylimidazole, m.p. 185°C. EXAMPLE 4

Compound H

A stirred suspension of 2-(1,3-dioxan-2-yl)- ethyltriphenylphosphonium bromide (2.3g) in anhydrous tetrahydrofuran (50ml) was flushed with argon and cooled to -10°C. Potassium t-butoxide (0.71g) was added in one portion, and the mixture was stirred at -10°C. for 1 hour. A solution of 4,5-diphenyl-1-[2- (trimethylsilyl)ethoxymethyl]-2-imidazolecarboxaldehyde (1.6g) in anhydrous tetrahydrofuran (10ml) was added dropwise during 2 to 3 minutes, maintaining the

temperature of the reaction mixture at or below 0°C.. After stirring for 30 minutes at 0°C, the mixture was diluted with saturated aqueous ammonium chloride solution. (50ml) and extracted with diethyl ether

(50ml). The organic layer was dried over magnesium sulphate and evaporated. The residue was subjected to flash chromatography, eluting first with a mixture of pentane and diethyl ether (1:1 v/v) to remove a faster-running minor component, which was discarded, and then with diethyl ether alone, gave an orange semisolid (1.2g).

A mixture of this product and tetrabutylammonium fluoride (1.0M in tetrahydrofuran; 16ml) in anhydrous tetrahydrofuran (25ml) was stirred at reflux for 6 hours. The dark mixture was evaporated to low bulk and partitioned between diethyl ether (50ml) and water (50ml). The diethyl ether layer was washed with water (2x50ml), dried over magnesium sulphate and evaporated. Crystallisation of the pale brown residue from toluene gave (E)-2-[3-(1,3-dioxan-2-yl)- propen-1-yl]-4,5-diphenylimidazole (0.48g) in the form of a cream solid, m.p. 174°C. [Elemental analysis:- C,76.2;H,6.44;N,8.0%; Calculated:- C,76.27;H,6.40;

N,8.09%; NMR (CDCl₃):- 1.36 (1H,m), 2.14 (1H,m), 3.83 (2H,m), 4.16 (2H,m), 4.69 (1H,t,J=5Hz), 6.46 (2H,m), 7.25-7.60 (10H,2m)].

EXAMPLE 5

Compounds I, J, K, and L

A mixture of 1-benzyl-4,5-diphenyl-2-(2-formyl- ethen-1-yl) imidazole (6.10g), ethylene glycol (5.2g), and pyridinium 4-toluenesulphonate (0.25g) in toluene (300ml) was stirred at reflux under a Dean and Stark water trap for 1.5 hours. After cooling to room temperature the mixture was diluted with ethyl acetate (300ml), washed with water (3x300ml), dried over magnesium sulphate and evaporated. Crystallisation from cyclohexane gave 1-benzyl-2-[2-(dioxolan-2-yl)- ethenyl]-4,5-diphenylimidazole (6.1g), m.p. 130°C.

A solution of 1-benzyl-2-[2-(dioxolan-2-yl)- ethenyl]-4,5-diphenylimidazole (5.0g) in ethyl acetate (200ml) was treated with 10% palladium on charcoal and the mixture was hydrogenated at room temperature until the uptake of hydrogen ceased (during 2 to 3 hours). The catalyst was removed by filtration through

diatomaceous earth and the residue was washed with fresh ethyl acetate. Evaporation of the combined filtrates gave a white solid (5.0g).

A portion of this solid (1.0g) was dissolved in anhydrous tetrahydrofuran (25ml), and ammonia (25 to 30ml) was condensed into the solution. Small pieces (50 to 60mg each) of sodium were added to the stirred mixture during 2 to 3 hours, each new piece only being added when the previous piece had completely dissolved. After 5 additions of sodium TLC analysis [silica gel plates, ethyl acetate eluant] showed that the reaction was complete. The mixture was then treated with solid ammonium chloride (5g) and the ammonia was allowed to evaporate. The residue was partitioned between ethyl acetate (50ml) and saturated aqueous ammonium chloride solution (25ml), and the ethyl

acetate layer was dried over magnesium sulphate and evaporated. The resulting residue was crystallised from a mixture of ethyl acetate and hexane (2:1 v/v), to give 2-[2-(dioxolan-2-yl)ethyl]-4,5-diphenylimidazole (0.19g), in the form of a white powder, m.p. 173-174°C. [Elemental analysis:- C,74.8;H,6.25;N,8.6%; Calculated:- C,74.97;H,6.29;N,8.74%; NMR (CD₃SOCD₃):- 2.04 (2H,m), 2.78 (2H,m,J=10Hz), 3.90 (4H,m), 5.93 (1H,t,J=6Hz), 7.2-7.5 (10H,m)].

By proceeding in a similar manner, but replacing the ethylene glycol by the appropriate quantity of the corresponding diols, there were also prepared:- 2-[2-(5,5-dimethyl-1,3-dioxan-2-yl)ethyl]-4,5-diphenyl- imidazole, m.p. 140-141°C.;

2-[2-(1,3-dioxan-2-yl)ethyl]-4,5-diphenylimidazole, m.p. 173-174°C; and

2-[2-(4,5-dimethyldioxolan-2-yl)ethyl]-4,5-diphenyl- imidazole, m.p. 151°C.

EXAMPLE 6

Compound M

A.stirred suspension of 2-(1,3-dioxan-2-yl)- ethyltriphenylphosphonium bromide (38.1g) in anhydrous tetrahydrofuran (500ml) was flushed with argon and cooled to -10°C. Potassium t-butoxide (12.0g) was added in one portion and the mixture was stirred at -10°C. for 1 hour. A solution of 1-benzy1-4,5- diphenyl-2-imidazolecarboxaldehyde (24.1g) in anhydrous tetrahydrofuran (100ml) was added dropwise during 2 to 3 minutes, maintaining the internal temperature at or below 0°C. After stirring for 30 minutes at 0°C the mixture was diluted with saturated aqueous ammonium chloride solution (500ml) and extracted with ethyl acetate (500ml). The organic layer was dried over magnesium sulphate and evaporated. The resulting pale red oil was passed rapidly down a short column of silica gel, eluting with diethyl ether. The

resulting solution was evaporated to dryness, to give a pale yellow powder (28.1g).

A portion (1.0g) of this powder was dissolved in ethyl acetate (25ml) and treated with 10% palladium on charcoal (0.1g). The mixture was hydrogenated at room temperature until hydrogen uptake ceased (2 hours). The catalyst was removed by filtration through diatomaceous earth and the residue was washed with ethyl acetate. Evaporation of the combined filtrates gave a cream solid (0.9g).

This solid was suspended in liquid ammonia (20ml) and the stirred mixture was treated with small pieces (6x30mg) of sodium, each piece only being added after the previous piece had completely dissolved.

The resulting dark brown solution was treated with solid ammonium chloride (5g) and the ammonia was allowed to evaporate. The residue was partitioned between dilute acetic acid (50ml: 2M) and ethyl acetate (50ml). The ethyl acetate layer was washed with water (25ml), dried over magnesium sulphate and

evaporated. Crystallisation of the residue from a mixture of ethyl acetate and hexane (1:1 v/v) gave 2-[3-(1,3-dioxan-2-yl)propyl]-4,5-diphenylimidazole (0.39g) in the form of a white solid, m.p. 204-205°C.; [Elemental analysis:- C,75.7;H,6.9;N,8.05%; Calculated:- C,75.83;H,6.94;N,8.04%; NMR (CDCl₃):- 1.2-2.2

(10H,m), 2.88 (2H,t,J=8HZ), 3.80 (2H,dt,J=12Hz, 3Hz), 4.14 (2H,dd,J=12Hz,5Hz), 4.65 (1H,t,J=6Hz), 7.2-7.6 (10H,m)].

EXAMPLE 7

Compounds N, O, P,and O

A solution of 1-benzyl-4,5-diphenylimidazole (27.0g) in anhydrous tetrahydrofuran (250ml) was

flushed with argon and cooled to -70°C. Butyllithium (2.6M solution in hexanes, 38.2ml) was added dropwise during 5 to 10 minutes, maintaining the internal temperature at or below -60°C.. After 15 minutes tetrahydro-4H-pyran-4-one (10.0g) was added dropwise, maintaining the internal temperature at or below

-60°C.. After 15 minutes the cooling bath was removed and the mixture was allowed to warm to room temperature. The mixture was partitioned between saturated aqueous ammonium chloride solution (250ml) and ethyl acetate (250ml). The organic layer was dried over magnesium sulphate.and evaporated. The crude product was triturated with hot ethyl acetate (200ml) and the mixture was allowed to stand overnight. Filtration gave 4-(1-benzyl-4,5-diphenylimidazol-2-yl)- 4-hydroxy-4H-tetrahydropyran (21.2g) in the form of white crystals, m.p. 145-146°C.

4-(1-benzyl-4,5-diphenylimidazol-2-yl)-4- hydroxy-4H-tetrahydropyran (19.8g) was dissolved in anhydrous tetrahydrofuran (100ml) and ammonia (350 to 400ml) was condensed into the solution. Small pieces of sodium were added to the stirred mixture during 2 to 3 hours, each new piece only being added when the previous piece had completely dissolved. When TLC analysis [silica gel plates, ethyl acetate eluant] showed that the reaction was complete, solid ammonium chloride (25g) was added and the ammonia was allowed to evaporate. The residue was partitioned between ethyl acetate (250ml) and saturated aqueous ammonium chloride solution (250ml), and the ethyl acetate layer was dried over magnesium sulphate and evaporated.

Crystallisation of the residue from ethanol gave

4-(4,5-diphenylimidazol-2-yl)-4-hydroxy-4H-tetrahydro- pyran (10.8g) in the form of a white crystalline solid, m.p. 221-2°C.

A stirred suspension of 4-(4,5-diphenylimidazol- 2-yl)-4-hydroxy-4H-tetrahydropyran (8.5g) in anhydrous dimethylformamide was cooled in an ice-bath and treated dropwise with trifluoroacetic anhydride (10ml) during 5 minutes. The cooling bath was removed and the mixture was stirred at room temperature. After 1 hour the mixture was poured slowly and cautiously onto a solution of potassium carbonate (50g) in water

(250ml), cooling with ice. The mixture was extracted with dichloromethane (250ml) and this solution was washed with water (2x200ml), dried over magnesium sulphate and evaporated. Crystallisation of the resulting residue from ethyl acetate gave

4-(4,5-diphenylimidazol-2-yl)-2H-5,6-dihydropyran

(5.0g), in the form of a white crystalline solid, m.p. 241°C; [Elemental analysis:- C,79.4;H,6.0; N,9.1%; Calculated:- C,79.44;H,6.00;N,9.27%

NMR (CDCl₃):- 2.66 (2H,m), 3.91 (2H,t,J=6Hz), 4.32 (2H,dt,J=6Hz,3Hz), 6.47 (1H,m), 7.2-7.6 (10H,2m)].

By proceeding in a similar manner, but replacing the tetrahydro-4H-pyran-4-one by the appropriate quantity of the corresponding cyclic ketones, there were prepared:-

1-(4,5-diphenylimidazol-2-yl)-4,4-dimethylcyclohexene, m.p. 259-260°C;

1-(4,5-diphenylimidazol-2-yl)cyclohexene, m.p. 256°C.; and 8-(4,5-diphenylimidazol-2-yl)-1,4-dioxaspiro- [4,5]dec-7-ene, m.p. 255°C. EXAMPLE 8

Compound R

A mixture of 1-(1-benzyl-4,5-diphenylimidazol- 2-yl)-4,4-dimethylcyclohex-2-enol (15.0g, m.p. 130°C, prepared from 1-benzyl-4,5-diphenylimidazole and

4,4-dimethylcyclohex-2-enone using the method given in Example 7), cyclohexene (25ml) and 10% palladium on charcoal (1.0g) in ethanol (150ml) was stirred at reflux for 48 hours. After cooling to room

temperature the mixture was filtered through

diatomaceous earth Evaporation of the filtrate gave a white solid, which was subjected to flash

chromatography on silica gel (using a mixture of

diethyl ether and dichloromethane; 1:20v/v; as eluent) and the second component obtained was crystallised from a mixture of ethyl acetate and cyclohexane, to give 1-(4,5-diphenylimidazol-2-yl)-4,4-dimethylcyclohexane (0.68g), in the form of a white crystalline solid, m.p. 232-233°C; [Elemental analysis:- C, 83.2;H, 8.0;

N,8.4%; Calculated:- C,83.59;H,8.0;N,8.4%].

EXAMPLE 9

Compound S

Liquid ammonia (ca. 300ml) was condensed into a stirred solution of [R,S]-1-benzyl-4,5-diphenyl-2-(tetra- hydropyran-2-yl) imidazole (9.0g) in anhydrous

tetrahydrofuran (75ml). Small pieces (ca. 100mg) of sodium were added, each addition being made only when the blue colour from the previous piece had been

completely discharged, until TLC analysis on silica gel plates, eluting with diethyl ether, showed that

reaction was complete. Solid ammonium chloride (20g) was added to the mixture and the ammonia was allowed to evaporate. The mixture was partitioned between water (200ml) and dichloromethane (300ml), and the organic layer was dried over magnesium sulphate and evaporated. Crystallisation of the resulting residue from ethyl acetate gave [R,S]-4,5-diphenyl-2-(tetrahydropyran-2-yl) imidazole (4.4g), in the form of a white crystalline solid, m.p. 193-194°C. [Elemental analysis: C,79.1; H,6.7;N,9.2%; Calculated:- C,78.9;H,6.6;N,9.2%].

EXAMPLE 10

Compounds T, U, V and W

By proceeding in a manner similar to that described hereinbefore in Example 9, but using the appropriate quantities of the corresponding 1-benzyl intermediates, there were prepared:- r-2-(4,5-diphenyl-2-imidazolyl)-5-methyl-t-5-[{2-(5- methyl-3-phenyl-1-pyrazolyl)ethoxy}methyl]-1,3-dioxane, m.p. 55-60°C;

r-2-(4,5-diphenyl-2-imidazolyl)-5-methyl-c-5-[{2-(5- methyl-3-phenyl-1-pyrazolyl)ethoxy}methyl]-1,3-dioxane, m.p. 40°C;

r-2-(4,5-diphenyl-2-imidazolyl)-5-methyl-c-5-[{2-(1- piperidinyl)ethoxy}methyl]-1,3-dioxane, m.p.

170-171°C; and

2-(4,5-diphenyl-2-imidazolyl)-5-(hydroxymethyl)-5-[{2- (4-morpholinyl)ethoxy}methyl]-1,3-dioxane, m.p.

107-110°C.

EXAMPLE 11

Compound X

A mixture of r-2-(1-benzyl-4,5-diphenyl-2- imidazolyl)-c-5-[{2-(3,5-dimethyl-1-pyrazolyl)ethoxy}- methyl]-5-methyl-1,3-dioxane (20g), limonene (40ml), and 10% palladium on charcoal catalyst (2.5g) in

dimethylformamide (500ml) was stirred at reflux for 5 hours. After cooling to room temperature, the mixture was filtered and the filtrate was evaporated to low bulk. The resulting dark oil was partitioned between water (250ml) and ethyl acetate (500ml), the layers separated, and the organic layer dried and evaporated. A small sample of the resulting residue was subjected to TLC analysis (ethyl acetate, silica gel plates), which showed one major new spot plus a considerable proportion of unreacted starting material. The rest of the said residue was subjected to flash chromatography (ethyl acetate) followed by crystallisation from cyclohexane, to give c-5-[(2-(3,5-dimethyl- 1-pyrazolyl)ethoxy)methyl]-r-2-(4,5-diphenyl-2-imidazolyl)-5-methy1-1,3-dioxane (6.0g) in the form of a sandy solid, m.p. 152-154°C. [Elemental analysis:- C, 71.5;H,6.96;N,11.7%; calculated:- C,71.2;H,6.8;N,11.9].

REFERENCE EXAMPLE 1

A stirred solution of 4,5-diphenylimidazole (2.2g) in dimethylformamide (20ml) was cooled in an ice-bath. Sodium hydride (0.36g of an 80% dispersion in oil) was added in small portions during 5 minutes. After stirring in the ice-bath for 1 hour the mixture was treated with 2-(trimethyIsilyl)ethoxymethyl

chloride (1.83g). The mixture was stirred at room temperature for 1 hour and then it was poured onto water (100ml) and extracted with diethyl ether (100ml). The organic phase was washed with water (2x50ml), dried, and evaporated to give a pale yellow oil, which crystallised on standing. Crystallisation from pentane gave 4,5-diphenyl-1-(2-(trimethylsilyl) ethoxymethyl)imidazole (2.0g), in the form of white needles, m.p. 69°C; [Elemental analysis:- C,71,7;H,7.3;

N,7.8%; Calculated:- C,71.95;H,7.48;N,7.99%].

A solution of 4,5-diphenyl-1-[2-(trimethylsilyl)ethoxymethyl]imidazole (1.75g) in anhydrous tetrahydrofuran (20ml) was flushed with argon and cooled to -70°C. Butyllithium (2.6ml of a 2.6M solution in hexanes) was added dropwise during 5 minutes. After stirring at.-70°C. for 10 minutes N-formylmorpholine (1.15g) was added during 2 to 3 minutes and stirring was continued at -70°C. for a further 15 minutes. The mixture was allowed to warm to room temperature during 1 hour and then it was partitioned between dilute hydrochloric acid (25ml;2M) and ethyl acetate (25ml). The organic layer was washed with sodium bicarbonate solution (25ml;5%w/v), and then with water (25ml), dried, and evaporated.

The resulting golden-coloured oil was passed rapidly down a short column of silica gel, eluting with a mixture of diethyl ether and pentane (1:3 v/v), to give 4,5-diphenyl-1-[2-(trimethylsilyl)ethoxymethyl]-2- imidazolecarboxaldehyde (1.6g) in the form of a sticky, colourless gum. This product was used immediately without further purification.

By proceeding in a similar manner, but using 1-benzyl-4,5-diphenylimidazole as a starting material, there was prepared 1-benzyl-4,5-diphenylimidazole-2- carboxaldehyde, m.p. 112-113°C. [Elemental analysis:- C,81.3;H,5.4;N,8.1%; Calculated:- C,81.6;H,5.36:

N,8.28%].

REFERENCE EXAMPLE 2

A stirred suspension of sodium hydride (1.14g of an 80% dispersion in oil) in anhydrous tetrahydrofuran was flushed with argon and cooled to -10°C. Triethyl phosphonoacetate (8.5g) was added dropwise during 10 minutes and the resulting mixture was stirred at -10°C. for 20 minutes. A solution of 4,5-diphenyl-1-[2- (trimethylsilyl)ethoxymethyl]-2-imidazolecarboxaldehyde (9.6g) in tetrahydrofuran (75ml) was added dropwise during 20 minutes whilst maintaining the internal temperature at or below -5°C.. After a further 30 minutes the solution was partitioned between saturated aqueous ammonium chloride solution (150ml) and diethyl ether (100ml). The organic phase was washed with water (50ml), dried, and evaporated. The residue was passed down a short column of silica gel, eluting with a mixture of diethyl ether and pentane mixture (1:3 v/v) to give (E)-4,5-diphenyl-2-[2-(ethoxycarbonyl)- ethenyl]-1-[2-(trimethylsilyl)ethoxymethyl]imidazole (9.7g) in the form of a cream solid, m.p. 132-133°C; [Elemental analysis:- C,70.1;H,7.3;N,6.1%; Calculated:- C,69.6;H,7.19;N,6.24%].

A solution of (E)-4,5-diphenyl-2-[2-(ethoxycarbonyl)ethenyl]-1-[2-(trimethylsilyl)ethoxymethyl]- imidazole (2.2g) in anhydrous tetrahydrofuran (40ml) was cooled to -40°C. and treated during 5 minutes with diisobutylaluminiumhydride (15ml of a 1.0M solution in toluene). After stirring at -40°C. for 1 hour the mixture was allowed to warm to -10°C. and then it was quenched by the slow addition of a saturated aqueous solution of sodium sulphate (100ml). The gelatinous mass was filtered through a filter aid and the residue was washed with a large volume of ethyl acetate. The combined filtrates were washed with water (50ml), dried, and evaporated to give (E)-4,5-diphenyl-2-(3- hydroxypropen-1-yl)-1-[2-(trimethylsilyl)ethoxymethyl]- imidazole (1.5g) in the form of a yellow solid, m.p. 128-129°C; [Elemental analysis:- C,70.9;H,7.6;

N,6.69%; Calculated:- C,70.9;H,7,44;N,6.89%].

By proceeding in a similar manner, but using 1-benzyl-4,5-diphenylimidazole as a starting material, there was prepared (E)-1-benzyl-4,5-diphenyl-2-(3- hydroxypropen-1-yl) imidazole, m.p. 199-200°C;

[Elemental analysis:- C,81.4;H, 6.05;N,7,4%;

Calculated:- C,81.9;H,6.05;N,7.65%].

REFERENCE EXAMPLE 3

(a) A solution of 1-benzyl-4,5-diphenyl-2-(3- hydroxypropen-1-yl)imidazole (12.0g) in anhydrous tetrahydrofuran (500ml) was flushed with argon and treated with manganese dioxide (38,5g) in one portion. The mixture was stirred at room temperature for

2 hours and then it was filtered through a bed of diatomaceous earth . The residue was washed with tetrahydrofuran (3x50ml) and the combined filtrates were evaporated to dryness, to give a yellow semisolid. This material was filtered through a small column of silica gel, eluting with a mixture of ethyl acetate and hexane (1:1 v/v), to give 1-benzyl-4,5-diphenyl-2-(2- formylethen-1-yl) imidazole (9.25g), in the form of a pale yellow powder, m.p. 149-150ºC.

(b) By proceeding in a similar manner, but using the appropriate quantity of (E)-4,5-diphenyl-2-(3-hydroxy- propen-1-yl)-1-[2-(trimethylsilyl)ethoxymethyl]- imidazole as starting material, there was prepared 1-[2-(trimethylsilyl)ethoxymethyl]-4,5-diphenyl-2-(2- formylethenyl)imidazole.

REFERENCE EXAMPLE 4

A stirred solution of 1-benzyl-4,5-diphenyl- imidazole (76.1g) in anhydrous tetrahydrofuran (500ml) was flushed with argon and cooled to -70ºC. Butyl- lithium (108ml of a 2.5 M solution in hexanes) was added dropwise at such a rate as to maintain the internal temperature at or below -60°C. After stirring at -70°C for 15 minutes 5-chloro-N-methyl-N- methoxypentanamide (50.6g) was added dropwise,

maintaining the internal temperature at or below -60°C. The mixture was stirred at -70°C for 30 minutes, allowed to warm to room temperature and was then partitioned between saturated aqueous ammonium chloride solution (250ml) and ethyl acetate (500ml). The organic layer was dried over magnesium sulphate and evaporated. The resulting residue was passed rapidly down a short column of silica gel, eluting with

dichloromethane. The fractions containing the product (determined by TLC analysis) were evaporated to dryness. Trituration of the residue with pentane gave 1-benzyl-2-(5-chloro-1-oxopentyl)-4,5-diphenyl- imidazole (87.7g), in the form of a white powder, m.p. 99-101°C.

Sodium borohydride (1.0g) was added to a stirred solution of 1-benzyl-2-(5-chloro-1-oxopentyl)-4,5- diphenylimidazole (20.0g) in ethanol (150ml) and

tetrahydrofuran (150ml). After l hour a further quantity of sodium borohydride (1.0g) was added.

After a further period of 1 hour at room temperature acetone (10ml) was added the mixture was evaporated to low bulk. The residue was partitioned between water (250ml) and dichloromethane (500ml), and the organic layer was dried over magnesium sulphate and evaporated, to give [R,S]-1-benzyl-2-(5-chloro-1-hydroxypentyl)-4,5- diphenylimidazole (20.0g), in the form of a white

powder, m.p. 118-119°C.

Sodium hydride (2.4g of a 60% dispersion in oil) was added to a stirred suspension of [R,S]-1-benzyl-2-(5- chloro-1-hydroxypentyl)-4,5-diphenylimidazole (17.0g) in anhydrous dimethylformamide (400ml). The mixture was warmed gently until gas evolution began, and then the mixture was stirred at room temperature for 2

hours. Excess sodium hydride was then destroyed by the cautious addition of a little water, and then the bulk of the solvent was removed on the rotary

evaporator. The residue was partitioned between water (250ml) and ethyl acetate (250ml), and the organic layer was dried over magnesium sulphate and evaporated. Trituration of the resulting golden- coloured oil with diethyl ether gave [R,S]-1-benzyl-4,5- diphenyl-2-(tetrahydropyran-2-yl) imidazole (9.1g), in the form of a white powder, m.p. 116°C.

REFERENCE EXAMPLE 5

A mixture of 1-benzyl-4,5-diphenyl-2-imidazole- carboxaldehyde (23.8g), 2-(bromomethyl)-2-(hydroxy- methyl)-1,3-propanediol (27.9g) and 4-toluenesulphonic acid (1.0g) in toluene (250ml) was stirred at reflux under a Dean and Stark water separator overnight.

After cooling to room temperature the mixture was treated with water (100ml) and shaken vigorously for 10 minutes. The resulting cream precipitate was

filtered off and washed thoroughly with water and then with toluene. The resulting white powder was

suspended in cyclohexane (250ml) and the mixture was stirred at reflux under a Dean and Stark water

separator until no more water separated. The mixture was allowed to cool to room temperature and the product was filtered off, to give 2-(1-benzyl-4,5-diphenyl)-5- (bromomethyl)-5-(hydroxymethyl)-1,3-dioxane (23.8g) in the form of an approximately 3:2 mixture of

diastereoisomers; m.p.181-185°C.

A mixture of 2-(1-benzyl-4,5-diphenyl)-5- (bromomethyl)-5-(hydroxymethyl)-1,3-dioxane (5.2g), ethyl vinyl ether (25ml), and pyridinium 4-toluene- sulphonate (1. 0g) in dichloromethane (50ml) and

tetrahydrofuran (75ml) was allowed to stand at room temperature overnight. The clear solution was evaporated to dryness and the residue was taken up in dichloromethane (100ml). This solution was washed with water (2x100ml), dried and evaporated. The residue was filtered through silica gel, eluting with a mixture of diethyl ether and pentane (1:1v/v) to give, after evaporation, a white foam (5.4g). This product was added to a solution of the sodium salt of

4-(2-hydroxyethyl)morpholine in dimethylformamide

(prepared from 2.3g of 4-(2-hydroxyethyl)morpholine and 0.71g of 60% sodium hydride in 50ml of dimethyIform- amide) and the resulting mixture was stirred at reflux for 45 minutes. After cooling to room temperature, the solvent was removed by evaporation and the residual oil was dissolved in tetrahydrofuran (50ml). The solution was treated with dilute hydrochloric acid (50ml;1.0M) and the resulting clear solution was allowed to stand at room temperature for 45 minutes. The mixture was basified by the cautious addition of solid potassium carbonate and then it was partitioned between water (50ml) and ethyl acetate (50ml). The layers were separated and the organic layer was washed with water, dried, and evaporated, to give 2-(1-benzyl- 4,5-diphenyl-2-imidazolyl)-5-(hydroxymethyl)-5-[(2-(4- morpholinyl)ethoxy)methyl]-1,3-dioxane (5.4g) in the form of a white foam.

The present invention also includes within its scope pharmaceutical formulations which comprise at least one of the compounds of formula I in association with a pharmaceutically acceptable carrier or coating. In clinical practice the compounds of the present invention may be administered parenterally, rectally or orally.

Solid compositions for oral administration include compressed tablets, pills, powders and

granules. In such solid compositions, one or more of the active compounds is, or are, admixed with at least one inert diluent such as starch, sucrose or lactose. The compositions may also comprise, as is normal practice, additional substances other than inert diluents, e.g. lubricating agents, such as magnesium stearate.

Liquid compositions for oral administration include pharmaceutically acceptable emulsions,

solutions, suspensions, syrups and elixirs containing inert diluents commonly used in the art such as water and liquid paraffin. Besides inert diluents such compositions may comprise adjuvants, such as wetting and suspending agents, and sweetening, flavouring, perfuming and preserving agents. The compositions according to the invention for oral administration also include capsules of absorbable material such as gelatin, containing one or more of the active

substances with or without the addition of diluents or excipients.

Compositions according to the invention for parenteral administration include sterile aqueous, aqueous-organic, and organic solutions, suspensions and emulsions. Examples of organic solvents or suspending media are propylene glycol, polyethylene glycol, vegetable oils such as olive oil and injectable organic esters such as ethyl oleate. The compositions may also contain adjuvants such as stabilising, preserving, wetting, emulsifying and dispersing agents. They may be sterilised, for Example, by filtration through a bacteria-retaining filter, by incorporation in the compositions of sterilising agents , by irradiation or by heating. They may also be manufactured in the form of sterile solid compositions, which can be dissolved in sterile water or some other sterile injectable medium immediately before use.

Solid compositions for rectal administration include suppositories formulated in accordance with known methods and containing at least one compound of formula I.

The percentage of active ingredient in the compositions of the invention may be varied, it being necessary that it should constitute a proportion such that a suitable dosage shall be obtained. Obviously, several unit dosage forms may be administered at about the same time. The size and frequency of the dose employed will be determined by the physician, and depends upon the desired therapeutic effect, the route of administration, the duration of the treatment and the age, sex, size and condition of the patient. In the adult, the doses are generally from about 0.5 to about 70, preferably about 1 to about 10, mg/kg body weight per day by oral administration.

The following Example illustrates a

pharmaceutical composition according to the present invention.

COMPOSITION EXAMPLE

No. 2 size gelatin capsules each containing:-

(E)-4,5-diphenyl-2-(2-phenylethenyl)imidazole 20 mg lactose 100 mg starch 60 mg dextrin 40 mg magnesium stearate 1 mg were prepared in accordance with the usual procedure.

Capsules can also be made up in a similar manner using any other of the compounds of the invention.

Claims

1. An imidazole derivative of the general formula :-

[DPIM]-X-Z-Y I wherein [DPIM] is of the general formula :

in which the symbols R¹ are the same or different and each represents a halogen atom or an alkyl or alkoxy group containing from 1 to 3 carbon atoms, the symbols n are the same or different and each represents 0 or an integer from 1 to 5, X represents a direct bond or an alkylene,

alkenylene or alkynylene group containing up to 3 carbon atoms, Z represents a direct bond or, when X is other than a direct bond, Z represents an oxygen atom, a group of formula -O-CH₂- or -NH-, and Y represents an alkoxycarbonyl group containing up to 5 carbon atoms, an optionally substituted alkyl group of up to 3 carbon atoms, an

optionally substituted phenyl or heterocyclyl group, or a group of the general formula :

wherein m represents 2, 3 or 4, the symbols p are the same or different and each represents 0, 1, 2, 3, 4 or 5, q represents 0 or 1, the symbols r are the same or different and each represents 1, 2, 3 or 4, provided that p, q and r are such that formulae III and IV each represents a 5-, 6- or 7-membered ring, and the symbols Q are the same or different and each represents a methylene group optionally substituted by one or two substituents selected from alkoxy groups of 1 to 5 carbon atoms and from optionally

substituted alkyl groups of 1 to 5 carbon atoms, or Q represents a methylene group substituted by each end of an alkylene chain of up to 8 carbon atons, optionally

interrupted by one or more double bonds and/or by one or more heteroatoms, and optionally substituted by one or more optionally substituted alkyl groups of 1 to 5 carbon atoms; and pharmaceutically acceptable acid addition salts

thereof; with the proviso that, when X represents a direct bond, R¹ is alkoxy, or Y is other than a 1,3-dioxocycloalk 2-yl group optionally substituted by one or more alkyl groups each of 1 to 3 carbon atoms and with the proviso that, when X represents a direct bond, Y is other than a 1,3-dioxan-2-yl group substituted on the 5-position by one or more alkyl groups containing from 1 to 3 carbon atoms substituted by one or more halogen atoms, by a hydroxy or acyloxy group, by an alkoxy group containing from 1 to 3 carbon atoms which itself is optionally substituted by a hydroxy or acyloxy group, or by a phenyl group which itself is optionally substituted by one or more substituents selected from halogen atoms and alkyl and alkoxy groups each containing up to 3 carbon atoms, and Y is other than a 1 , 3-dioxan-2-yl group substituted on the 5-position by an alkylene or alkenylene chain which together with the carbon atom to which it is attached forms a cycloalkane or

cycloalkene group containing from 5 to 7 carbon atoms; and pharmaceutically acceptable salts thereof.

2. A compound according to claim 1 wherein the symbols R¹ are the same or different and each represents a halogen atom or an alkyl or alkoxy group containing from 1 to 3 carbon atoms, the symbols n are the same or different and each represents 0 or an integer from 1 to 5, X

represents a direct bond or an alkylene, alkenylene or alkynylene group containing up to 3 carbon atoms, Z

represents a direct bond or, when X is other than a direct bond, Z represents an oxygen atom, a group of formula

-O-CH₂- or -NH-, and Y represents an alkoxycarbonyl group containing up to 5 carbon atoms, an alkyl group of up to 3 carbon atoms optionally substituted by one or more alkoxy groups each containing up to 3 carbon atoms, an optionally substituted phenyl or heterocyclyl group, or a group of the general formula II, III or IV, wherein m represents 2, 3 or 4, the symbols p are the same or different and each represents 1, 2, 3, 4 or 5, q represents 0 or 1, the symbols r are the same or different and each represents 1, 2, 3 or 4, provided that p, q and r are such that formulae III and IV each represents a 5-, 6- or 7-membered ring, and the symbols Q are the same or different and each represents a methylene group optionally substituted by one or two substituents selected from alkoxy groups of 1 to 5 carbon atoms and from alkyl groups of 1 to 5 carbon atoms

optionally substituted by one or more substituents selected from hydroxy groups, alkoxy groups of 1 to 5 carbon atoms (which themselves may each be substituted, by a

heterocyclyl group), or Q may be substituted by each end of an alkylene chain, to form a spirane ring, optionally interrupted by one or more heteroatoms, and optionally substituted by one or more alkyl groups of 1 to 5 carbon atoms optionally substituted by one or more substituents selected from hydroxy groups, alkoxy groups of 1 to 5 carbon atoms, amino groups, alkylamino groups of 1 to 5 carbon atoms, and dialkylamino groups of 1 to 5 carbon atoms in each alkyl moiety, with the proviso that, when X represents a direct bond, R¹ is alkoxy, or Y is other than a 1,3-dioxocycloalk-2-yl group optionally substituted by one or more alkyl groups each of 1 to 3 carbon atoms and with the proviso that Y is other than a 1,3-dioxan-2-yl group substituted on the 5-position by one or more alkyl groups containing from 1 to 3 carbon atoms substituted by one or more halogen atoms, by a hydroxy or acyloxy group, by an alkoxy group containing from 1 to 3 carbon atoms which itself is optionally substituted by a hydroxy or acyloxy group, or by a phenyl group which itself is

optionally substituted by one or more substituents selected from halogen atoms and alkyl and alkoxy groups each

containing up to 3 carbon atoms, and Y is other than a 1,3- dioxan-2-yl group substituted on the 5-position by an alkylene or alkenylene chain which together with the carbon atom to which it is attached forms a cycloalkane or

cycloalkene group containing from 5 to 7 carbon atoms.

3. A compound according to claim 1 or 2

wherein:

in the definition of Y, optionally substituted alkyl groups are optionally substituted by one or more alkoxy groups each containing up to 3 carbon atoms; and the heterocyclyl group is pyridyl;

in the definition of the symbol Q optionally substituted alkyl groups are optionally substituted by one or more substituents selected from halogen atoms, hydroxy groups, acyloxy groups, alkoxy groups of 1 to 5 carbon atoms (which themselves may each be substituted by a hydroxy or acyloxy group, or by a heterocyclyl group which itself is optionally substituted by one or more

substituents selected from alkyl groups containing up to 3 carbon atoms and optionally substituted phenyl groups), and phenyl groups (which themselves are optionally substituted by one or more substituents selected from halogen atoms and alkyl and alkoxy groups each containing up to 3 carbon atoms); heteroatoms are nitrogen, sulphur or oxygen; and the alkylene chain in the definition of Q is optionally substituted by one or more alkyl groups of 1 to 5 carbon atoms which groups are optionally substituted by one or more. substituents selected from hydroxy groups, alkoxy groups of 1 to 5 carbon atoms, amino groups, alkylamino groups of 1 to 5 carbon atoms, and dialkylamino groups of 1 to 5 carbon atoms in each alkyl moiety.

4. A compound according to claim 1, 2 or 3, wherein acyloxy groups are alkanoyloxy of up to 6 carbon atoms or benzoyloxy.

5. A compound according to claim 1, 2, 3 or 4 wherein at least one of the symbols has a value selected from the following:-

(i) n represents 0;

(ii) Z represents a direct bond;

(iii) Y represents an alkoxycarbonyl group, or a substituted or unsubstituted phenyl or heterocyclyl group, or a group of the general formula II, III or IV;

(iv) m represents 2 or 3;

(v) p represents 0 or 4; and

(vi) Q represents a methylene group optionally substituted by one or two substituents selected from alkyl groups [optionally substituted by one or two substituents selected from hydroxy groups, and from alkoxy groups (which themselves may be substituted by a heterocyclyl group which itself is optionally substituted by one or more

substituents selected from alkyl groups and substituted and unsubstituted phenyl groups)]; or Q represents a methylene group substituted by each end of a 1,2-ethylenedioxy chain; the other symbols being as defined in claim 1, and

pharmaceutically acceptable acid addition salts thereof.

6. A compound according to claim 5 wherein: in the definition of Y the alkoxycarbonyl group is ethoxycarbonyl, the phenyl or heterocyclyl group is unsubstituted, and the heterocyclyl group is pyridyl; in the definition of Q the methylene group is optionally substituted by one or two methyl groups, the alkoxy group is ethoxy, the heterocyclyl group is pyrazolyl, morpholinyl or piperidinyl optionally substituted by one or more substituents selected from methyl groups and unsubstituted phenyl groups.

7. A compound according to claim 1

hereinbefore identified as any one of A to X or a

pharmaceutically acceptable acid addition salt thereof.

8. A process for the preparation of a compound according to claim 1 which comprises:

(a) the replacement by a hydrogen atom of a group R² in a compound of the general formula :

wherein R¹, n, X, Z and Y are as defined in claim 1 and R² represents a protecting group;

(b) when X represents a vinylene or ethynylene group, Z represents a direct bond and Y represents an optionally substituted phenyl or heterocyclyl group,

[DPIM], R¹ and n being as defined in claim 1, the reaction of a compound of the general formula :

wherein R¹ and n are as defined in claim 1, with a compound of the general formula :

Y¹-X¹-CHO VII wherein X¹ represents a vinylene or ethynylene group and Y¹ represents an optionally substituted phenyl or heterocyclyl group and a source of ammonia;

(c) when Y represents a group of formula IV depicted in claim 1, X and Z each represents a direct bond, and [DPIM], R¹, n, X, Z, Q, q and r are as defined in claim 1, by the dehydration of a compound of the general formula:

wherein [DPIM], Q, g and r are as defined in claim 1;

(d) when X and Z each represents a direct bond, Y represents a group of formula III as defined in claim 1 wherein q represents 0, p+p=3,4,5, or 6, and Q and [DPIM] are as defined in claim 1, by the reduction of a compound of general formula :

wherein p¹ represents 2, 3, 4 or 5, R³ represents a

hydrogen atom or a protecting group, and R¹, n and Q are as defined in claim 1.

9. A pharmaceutical composition which comprises an imidazole derivative of general formula I as defined in claim 1, or a pharmaceutically acceptable acid addition salt thereof, in association with a

pharmaceutically acceptable carrier or coating.

10. A pharmaceutical composition useful in the treatment of a condition which can be ameliorated by the administration of an inhibitor of acyl coenzyme- A:cholesterol-O-acyl transferase or of an inhibitor of the binding of thromboxane TXA₂ to its receptors, which

comprises an amount effective to ameliorate said condition of an imidazole derivative of general formula I as defined in claim 1 or a pharmaceutically acceptable acid addition salt thereof, in association with a pharmaceutically acceptable carrier or coating.

11. An imidazole derivative of general formula I as defined in claim 1 or a pharmaceutically acceptable acid addition salt thereof, for use in therapy.

12. An imidazole derivative of general formula I as defined in claim 1 or a pharmaceutically acceptable acid addition salt thereof, for use in therapy for the treatment of a condition which can be ameliorated by the administration of an inhibitor of acyl coenzyme- A:cholesterol-O-acyl transferase or of an inhibitor of the binding of thromboxane TXA₂ to its receptors

13. A method for the treatment of a human or animal patient suffering from, or subject to, a condition which can be ameliorated by the administration of an inhibitor of acyl coenzyme-A:cholesterol-O-acyl transferase or of an inhibitor of the binding of thromboxane TXA₂ to its receptors, which comprises administering to the patient an effective amount of an imidazole derivative of general formula I or a pharmaceutically acceptable acid addition salt thereof.