WO1992004330A1

WO1992004330A1 - Substituted imidazoles, their preparation and pharmaceutical compositions

Info

Publication number: WO1992004330A1
Application number: PCT/GB1991/001546
Authority: WO
Inventors: Deidre Mary Bernadette HICKEY; David Gwynn Cooper; Caroline Marie Whittaker
Original assignee: Smith Kline & French Laboratories Limited
Priority date: 1990-09-11
Filing date: 1991-09-10
Publication date: 1992-03-19
Also published as: JPH06500995A; EP0550502A1; GB9019840D0; AU8522491A

Abstract

Substituted 4,5-diaryl-1-carboxyalkylimidazoles, of structure (I), in which each group Ar is the same or different and is optionally substituted phenyl or optionally substituted heteroaryl or, when both groups Ar are phenyl they can be linked by a bond; R is hydrogen, alkyl, alkoxy, alkyl, optionally substituted phenyl, phenyl alkyl in which the phenyl group is optionally substituted, alkylCHO or alkylCH(OR1)(OR2) in which each group R?1 and R2¿ is alkyl, or together form an ethane 1,2-diyl or propane 1,3-diyl group; n is 2 to 6 and m is 0 to 6; R?3, R4, R5 and R6¿ are the same or different and are each hydrogen or alkyl; AB is a bond, -C=C-, -CH=CH-, S, O, SPh or OPh; and X is CO¿2?H or a group hydrolysable to CO2H, 5-tetrazolyl, SO3H, P(O)(OR)2, P(O)(OH)2, or P(O)(R)(OR) in which R is hydrogen or alkyl, or a pharmaceutically acceptable salt thereof, processes for preparing them, pharmaceutical compositions containing them and their use in therapy, inter alia, in the treatment of cardiovascular disorders.

Description

SUBSTITUTED IMIDAZOLES, THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS

The present invention relates to novel substituted imidazole compounds, processes for their preparation, pharmaceutical compositions containing them and their use in therapy.

The present invention therefore provides in a first aspect compounds of structure (I) :

in which each group Ar is the same or different and is optionally substituted phenyl or optionally substituted heteroaryl or, when both groups Ar are phenyl they can be linked by a bond;

R is hydrogen, C₁_₈alkyl, C₁_₈alkoxy, SC₁_₈alkyl, optionally substituted phenyl, phenyl C₁_ alkyl in which the phenyl group is optionally substituted, C .galkylCHO or C-_j^gal ylCHfOR¹) (OR²) in which each group R¹ and R² is C-*^alkyl, or together form an ethane 1,2-diyl or propane 1,3-diyl group; n is 2 to 6 and m is 0 to 6;

R⁴, R⁵ and R⁶ are the same or different and are each hydrogen or C--^alkyl; AB is a bond, -CΞC-, -CH=CH-, S, 0, SPh or OPh; and X is C0₂H or a group hydrolysable to C0₂H,

5-tetrazolyl, S0₃H, P(0) (OR)₂, P(0)(OH)₂, or P(0) (R) (OR) in which R is hydrogen or C₁_₄alkyl, or a pharmaceutically acceptable salt thereof. Suitably, each group Ar is the same and is optionally substituted phenyl or optionally substituted heteroaryl. More suitably, each group Ar is the same and is optionally substituted phenyl. Preferably each group Ar is the same and is unsubstituted phenyl.

Suitably, R is hydrogen, C-^galkyl, C-_j^alkoxy, SC₁_₈alkyl, optionally substituted phenyl, phenyl C*L_ alkyl ^ⁿ whi⁰*¹ the phenyl group is optionally substituted, C-^galkylCHO or C₁_₆alkylCH(OR¹) (OR²) in which each group R¹ and R² is C₁_₄alkyl, or together form an ethane 1,2-diyl or propane 1,3-diyl group. Preferably R is C₁_₄alkyl or optionally substituted phenyl.

Suitably, n and together are 4 to 12, preferably 4 to 8, and most preferably 6 or 7.

Suitably, R³, R⁴, R⁵ and R⁶ are the same or different and are each hydrogen or C_1-4alkyl. Preferably, R³, R⁴, R⁵ and R⁶ are the same and are each hydrogen.

Suitably, AB is a bond, -C=C-, -CH=CH-, S, 0, SPh or OPh. Preferably, AB is a bond or S; most preferably AB is a bond.

Suitably, X is C0₂H or a group hydrolysable to C0₂H, 5-tetrazolyl, S0₃H, P(0)(OR)₂, P(0)(0H)₂, or P(0) (R) (OR) in which R is hydrogen or C₁_₄alkyl.

Preferably X is C0 H, a group hydrolysable to C0₂H or 5-tetrazolyl. Suitable substituents for phenyl groups Ar and R include, for example, 1-3 groups which may be the same or different and are selected from C₁_₄alkyl, haloC_1-4alkyl such as CF₃, halogen, hydroxy and C_1-4alkoxy.

Suitable heteroaryl groups include, for example, saturated or unsaturated 5- or 6-membered rings comprising 1 to 3 heteroatoms selected from nitrogen, oxygen and sulphur. Preferred such rings include, for example, thienyl and furyl rings.

Suitable groups X, hydrolysable to C0₂H include for example, nitriles, amides and ester groups. Examples of ester groups are C-^.galkyl esters and optionally substituted benzyl esters. Particular ester groups include mono-C₁_₄alkoxycarbonyl groups such as ethoxycarbonyl and methoxycarbonyl, and tri-C₁_₄alkoxy carbonyl groups such as methoxyethoxyethoxy carbonyl

O

II groups (CH₃0(CH₂)₂0(CH )₂0-C-) .

The compounds of structure (I) can be prepared using procedures analogous to those known in the art. The present invention therefore provides in a further aspect a process for the preparation of compounds of structure (I) which comprises:

(a) for compounds other than those in which X is 5-tetrazolyl, reaction of a compound of structure (II) :

in which Ar, R, R³, R⁴, R⁵, R⁶, AB, N and m are as described for structure (I) and L is a leaving group, with a suitable source of the group X;

(b) reaction of a compound of structure (III) :

H

in which Ar and R are as described for structure (I) with a compound of structure (IV) :

L(CR³R⁴)_nAB(CR⁵R⁶)_mX (IV)

in which R³, R⁴, R⁵, R⁶, AB, n, and X are as described for structure (I) and L is a leaving group; or

(c) for compounds in which A is other than a bond or -CH=CH-, reaction of a compound of structure (V) :

in which Ar, R, R³, R⁴ and n are as described for structure (I) and L is a leaving group, with a compound of structure (VI) :

(VI) in which A^¹ is -CΞC-, S, O, SPh or OPh, R⁵,

R⁶, m and X are as described for structure (I) and L' is hydrogen or a metal;

(d) for compounds in which X is 5-tetrazolyl reaction of a compound of structure II in which L is CN, with tri-n-butyl tin azide, and optionally thereafter converting one group X into another group X, and optionally forming a salt.

Suitable leaving groups L will be apparent to those skilled in the art and include, for example, halogen, such as bromine, and sulphonic acid derivatives such as tosylate and mesylate.

Suitable metals include, for example, alkali metals such as sodium or lithium.

Suitable sources of the group X will again be apparent to those skilled in the art and include, for example, where X is S0₃Na, sodium sulphite.

The reaction between the compounds of structure (II) and the source of X is carried out in a solvent at elevated temperature. Preferably, for example where X is S0₃Na the reaction is carried out in aqueous ethanol at reflux temperature for a suitable period to allow the reaction to go to completion; and where X is a phosphorus containing group the reaction is carried out in an organic solvent such as toluene or xylene.

The reaction between compounds of structure (III) and structure (IV) can be carried out in an organic solvent in the presence of a base, at a temperature of between ambient and the reflux temperature of the solvent used. Suitable solvents include, for example, C₁_ alkanols such as methanol or ethanol, dimethyl formamide and butanone, and suitable bases include, for example, potassium carbonate, sodium hydroxide and sodium hydrid .

The reaction between compounds of structure (V) and structure (VI) is carried out in a suitable solvent in the presence of a base at a temperature of between ambient and the reflux temperature of the solvent used. Suitable solvents and reagents include, for example, potassium carbonate as the base in butanone as solvent, and sodium in methanol as a solvent.

Compounds of structure (I) in which X is 5-tetrazolyl, can be prepared from compounds of structure (II) by standard techniques, for example, when L is bromine, by reaction with sodium cyanide in a suitable solvent such as di ethylsulphoxide, to form the intermediate compound in which L is cyano; followed by reaction with tri-n-butyl tin azide in, for example, tetrahydrofuran to form the desired compound of structure (I) .

The intermediate compounds of structures (II) , (III) , (IV) , (V) and (VI) are known or can be prepared by standard techniques.

The compounds of structure (I) and their pharmaceutically acceptable salts have been found to be PGI₂ agonists and as such are useful in therapy for the treatment of disease conditions in which such an effect is beneficial. More specifically, the compounds are expected to have utility as antithrombotic, vasodilatory, anti- atherosclerotic, antiinflam atorv a d cytoprotective agents. In particular, as anti arombotic and vasodilatory agents, the compounds are expected to be useful in the treatment of cardiovascular occlusive disorders including spasmodic and thrombotic disorders; coronary heart disease (primary and secondary prevention) ; stroke; post-operative thrombosis utilisation including post-angioplasty; deep vein thrombosis; peripheral vascular disease and Reynaud's disease. As antiathero- sclerotic agents the compounds would be expected to reduce atherosclerotic plaque formation; and as cytoprotective agents the compound'*' would be expected to protect liver and gastric mucosa, p otect against mucosal and ulcerative damage and reduce infarct size in myocardial infarct.

In addition to the foregoing utilities the compounds have antihyperlipidaemic properties and as such are expected to be of use as lipid lowering agents, and in the treatment of atherosclerosis and its sequelae.

In therapeutic use, the compounds of the present invention are usually administered in a standard pharmaceutical composition. The present invention therefore provides in a further aspect pharmaceutical compositions comprising a compound of structure (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

The compounds of structure (I) and their pharmaceutically acceptable salts which are active when given orally can be formulated as liquids, for example syrups, suspensions or emulsions, tablets, capsules and lozenges.

A liquid formulation will generally consist of a suspension or solution of the compound or pharmaceutically acceptable salt in a suitable liquid carrier(s) for example, ethanol, glycerine, non-aqueous solvent, for example polyethylene glycol, oils, or water with a suspending agent, preservative, flavouring or colouring agent.

A composition in the form of a tablet can be prepared using any suitable pharmaceutical carrier(s) routinely used for preparing solid formulations. Examples of such carriers include magnesium stearate, starch, lactose, sucrose and cellulose.

A composition in the form of a capsule can be prepared using routine encapsulation procedures. For example, pellets containing the active ingredient can be prepared using standard carriers and then filled into a hard gelatin capsule; alternatively, a dispersion or suspension can be prepared using any suitable pharmaceutical carrier(s), for example aqueous gums, celluloses, silicates or oils and the dispersion or suspension then filled into a soft gelatin capsule.

Typical parenteral compositions consist of a solution or suspension of the compound or pharmaceutically acceptable salt in a sterile aqueous carrier or parenterally acceptable oil, for example polyethylene glycol, polyvinyl pyrrolidone, lecithin, arachis oil or sesame oil. Alternatively, the solution can be lyophilised and then reconstituted with a suitable solvent just prior to administration. A typical suppository formulation comprises a compound of structure (I) or a pharmaceutically acceptable salt thereof which is active when administered in this way, with a binding and/or lubricating agent such as polymeric glycols, gelatins or cocoa butter or other low melting vegetable or synthetic waxes or fats.

Preferably the composition is in unit dose form such as a tablet or capsule.

Each dosage unit for oral administration contains preferably from 1 to 250 mg (and for parenteral administration contains preferably from 0.1 to 25 mg) of a compound of the structure (I) or a pharmaceutically acceptable salt thereof calculated as the free base.

The present invention also provides a method of mimicking the effects of PGI₂ which comprises administering to a mammal in need thereof an effective amount of a compound of the structure (I) or a pharmaceutically acceptable salt thereof; and a method of treatment of cardiovascular disorders which comprises administering to a mammal in need thereof an effective amount of a compound of the structure (I) or a pharmaceutically acceptable salt thereof.

The pharmaceutically acceptable compounds of the invention will normally be administered to a subject in a daily dosage regimen. For an adult patient this may be, for example, an oral dose of between 1 mg and 500 mg, preferably between 1 mg and 250 mg, or an intravenous, subcutaneous, or intramuscular dose of between 0.1 mg and 100 mg, preferably between 0.1 mg and 25 mg, of the compound of the structure (I) or a pharmaceutically acceptable salt thereof calculated as the free base, the compound being administered 1 to 4 times per day. Suitably the compounds will be administered for a period of continuous therapy, for example for a week or more.

The following Examples serve to illustrate the invention. Temperatures are recorded in degrees centigrade.

Example 1

A fixture of 2,4,5-triphenylimidazole (llg) , ethyl 8-brom octanoate (18.64g), anhydrous potassium carbonate (51.3g) and dry butanone (350ml) was heated at reflux for 26h. The cooled reaction mixture was filtered to remove inorganics and the filtrate was evaporated to dryness in vacuo. The residue was stirred in hexane and unreacted 2,4,5-triphenylimidazole was collected by filtration (3.lg). The filtrate was cooled and a white precipitate was collected. Recrystallisation from hexane gave 1-(7-ethoxycarbonylheptyl)-2,4,5-triphenylimidazole (8.37g, 48.4%) as a white solid, m.p. 65-7°. Found C, 79.97; H, 7.32; N, 6.39%; ^c _3l ^H ₃4^N2°2 requires: C, 79.79; ^"I, 7.34; N, 6.00%.

Example 2

A mixture of l-(7-ethoxycarbonylheptyl)-2,4,5- triphenylimidazole (13.6g), 2N aqueous sodium hydroxide (300ml) and ethanol (200ml) was heated at reflux for 2.5h. The ethanol was removed in vacuo and the reaction mixture was acidified with 2N aqueous hydrochloric acid. The aqueous solution was extracted with ethyl acetate (4 x 200ml) and the organic extracts were combined, dried over anhydrous magnesium sulphate and evaporated to dryness in vacuo. Recrystallisation from ethanol gave 1-(7-carboxyheptyl)-2,4,5-triphenylimidazole (9.77g, 76.4%) as a white solid, m.p. 162°. Found C, 79.43; H, 6.93; N, 6.36%;

^C29^H30^N2°2 requires: C, 79.42; H, 6.90; N, 6.39%. Example 3

A mixture of l-(7-carboxyheptyl)-2,4,5-triphenyl- imidazole (0.5g), concentrated sulphuric acid (2ml) and methanol (100ml) was heated at reflux for 24h. The solvent was removed in vacuo and the residue was dissolved in ethyl acetate (50ml) , washed with water (50ml) , saturated NaHC0₃ solution (50ml) , water (50ml) , dried over anhydrous magnesium sulphate and evaporated to dryness in vacuo. Column chromatography on silica gel eluted with a dichloromethane: ethanol gradient gave 1-(7-methoxycarbonylheptyl)-2,4,5-triphenylimidazole (0.28g, 54%) as an oil. Found: C, 79.74; H, 7.55; N, 5.99%; C₃₀H ₂N₂0 requires: C, 79.61; H, 7.13; N, 6.19%.

Example 4

2,4,5-Triphenylimidazole (l.3g) was added to a suspension of sodium hydride (0.23g) (50% dispersion in oil, washed with hexane) in dry dimethylformamide (40ml) under nitrogen. The reaction was stirred at 45°C for 1.5h, cooled and ethyl 7-bromoheptanoate (l.lg) in dry dimethylformamide (10ml) was added. The reaction was stirred at 50°C for 5h, cooled and water was carefully added. The solvent was removed in vacuo and the residue was dissolved in ethyl acetate (100ml) . The organic solution was washed with saturated sodium chloride solution (150ml) , water (100ml) , dried over anhydrous magnesium sulphate and evaporated to dryness in vacuo.

The residue was chromatographed on silica gel eluted with a dichloromethane:ethanol gradient to give l-(6-ethoxy- carbonylhexyl)-2,4,5-triphenylimidazole (0.81g, 41%) as an oil. Found: C, 79.74; H, 7.32; N, 6.12%;

^C ₃₀ ^H ₃₂ ^N ₂°₂ requires: C, 79.61; H, 7.13; N, 6.19%.

Example 5

Reaction of 1-(6-ethoxycarbonylhexyl)-2,4,5- triphenylimidazole (0.4g) with sodium hydroxide in a method similar to Example 2 gave, after recrystallisations from ethanol and isopropanol, l-(6-carboxyhexyl)-2,4,5- triphenylimidazole (0.19g, 51%) as a white solid, m.p. 149-150°.

Found: C, 79.34; H, 6.65; N, 6.48%; ^C2₈ ^H28^N2°2 requires: C, 79.22; H, 6.65; N, 6.60%.

Example 6

a) A mixture of 2,4,5-triphenylimidazole (52.5g), dibromohexane (174g) and potassium carbonate (48.4 g) in dry butanone (400 ml) were heated at reflux temperature for 20 hours. The mixture was filtered and the filtrate evaporated to an oil. Approximately half of the excess dibromohexane was removed by distillation and the remaining oil was chromatographed on silica gel (hexane/ethyl acε ate) giving, after recrystallisation from ethyl acetate, l-(6-bromohexyl)-2,4,5-triphenyl- imidazole (35.Og, 43%) as a colourless solid, m.p. 106-7°C. MR δ (CDC1₃) 0.9-1.7 (8H, m, 4 x CH₂) , 3.2 (2H, t, CH₂Br) , 3.9 (2H, t, CH₂N) , 7.1-7.7 (15H, m, 3 x Ph) pp .

b) l-(6-Bromohexyl)-2,4,5-triphenylimidazole (27.6g) in dry dimethylsulphoxide (70ml) was added over 10 minutes to a mixture of sodium cyanide (3.68g) in dimethyl- sulphoxide (50ml) and the reaction was stirred at room temperature for 2Oh. The reaction mixture was poured into water (300ml) and extracted with dichloromethane (3 x 150ml) . The extracts were combined, washed with water, dried over anhydrous magnesium sulphate and evaporated to dryness in vacuo. Recrystallisation from diethyl ether and hexane gave 1-(6-cyanohexyl)-2,4,5- triphenylimidazole (24.19g, 99%) as a white solid, m.p. 104-6°.

NMR δ (CDC1₃) 0.8-1.1 (4H, m, 2 X CH₂) , 1.1-1.4 (4H, m, 2 x CH₂), 2.1 (2H, t, CH₂CN) , 3.90 (2H, t, NCH₂) 7.0-7.8(15H, m, 3 x Ph) pp

c) A mixture of l-(6-cyanohexyl)-2,4,5-triphenyl- imidazole (2g) , tri-n-butyl tin azide (5g) (Kricheldorf, H, Leppert, E, Synthesis, (1976) 329) and dry tetrahydrofuran (10ml) , under nitrogen, was heated at reflux for 2Oh. Tri-n-butyl tin azide (5g) in dry tetrahydrofuran (10ml) was added and the reaction was heated at reflux for 24h. The cooled reaction mixture was poured into 2N aqueous hydrochloric acid (100ml) and water (100ml) was added. The aqueous mixture was extracted with dichloromethane (2 x 50ml) . The organic extracts were combined, washed with saturated sodium chloride solution (50 ml) dried over anhydrous magnesium sulphate and evaporated to dryness in vacuo.

Chromatography on silica gel eluted with a dichloro¬ methane:methanol gradient and recrystallisation from ethanol/water gave l-[6-(5-tetrazolyhexyl)-2,4,5- triphenylimidazole (0.25g, 11.4%) as a white solid, m.p. 196-7°.

Found: C, 75.07; H, 6.40; N, 18.61%;

C₂₈H₂₈N₆ requires: C, 74.97; H, 6.29; N, 18.74%. Example 7

a) 2,4,5-Triphenylimidazole (5g) was added to a suspension of sodium hydride (l.Og) (50% dispersion in oil, washed with hexane) in dry dimethylformamide (80ml) under nitrogen. The reaction was stirred at 45°C for lh, cooled and added, over lh to a solution of 1,8-dibromo- octane (30g) in dry dimethylformamide (100ml) under nitrogen. The reaction was stirred at room temperature for 24h, water was carefully added and the solvent was removed in vacuo. The residue was dissolved in ethyl acetate (500ml) , washed with water (250ml) , 2N aqueous hydrochloric acid (250ml) , saturated sodium chloride solution (250ml) , dried over anhydrous magnesium sulphate and evaporated to dryness in vacuo. Distillation to remove 1,8-dibromooctane and chromatography on silica gel eluted with dichloromethane gave 1-(8-bromooctyl)-2,4,5- triphenylimidazole (4.1g, 50%) as an oil. NMR 6 (CDC1₃) 0.9-1.7 (12H, m, 6 X CH₂) , 3.3 (2H, t, BrCH₂), 3.9 (2H, t, N-CH₂) , 7.1-7.7(15H, m, 3 x Ph) pp .

b) l-(8-Bromooctyl)-2,4,5-triphenylimidazole (4g) in dimethylsulphoxide (30ml) was added dropwise to a mixture of sodium cyanide (0.5g) in dry dimethylsulphoxide (30ml) . The reaction mixture was stirred at 50°C for 2h, cooled and poured into water (400ml) . The aqueous was extracted with diethyl ether (4 x 100ml) , the extracts were combined, washed with water (100ml) , dried over anhydrous magnesium sulphate and evaporated to dryness in vacuo. Chromatography on silica gel eluted with a dichloromethane:methanol gradient and recrystallisation from ether gave l-(8-cyanoctyl)-2,4,5-triphenylimidazole (l.lg, 31%) as a white solid, m.p. 72-73°. Found: C, 83.10; H, 7.21; N, 9.69%; ₃₀H₃₁N₃ requires: C, 82.90; H, 7.19; N, 9.57%. c) A mixture of l-(8-cyanooctyl)-2,4,5-triphenyl- imidazole (0.8g), concentrated sulphuric acid (10ml) and water (10ml) was stirred at reflux for 4h. Water (50ml) was added to the cooled mixture and the mixture was extracted with ethyl acetate (2 x 25ml) . The organic extracts were combined, washed with water (25ml) , dried over anhydrous magnesium sulphate and evaporated to dryness in vacuo. Recrystallisation from ethanol/water gave l-(8-carboxyoctyl)-2,4,5-triphenylimidazole (0.22 g, 26%) as a cream solid, m.p. 149-150°. Found C: 79.32; H, 7.17; N, 5.95%; C₃₀H₃₂N₂ requires: C, 79.61; H, 7.13; N, 6.19%.

Example 8

(a) 2,4,5-Triphenylimidazole (2.5g) and ethyl 11-bromoundecanoate (4.94g) were reacted in a method similar to Example 1. Work-up and column chromatography on silica gel eluted with 30:1 dichloromethane:ethanol gave 1-(10-ethoxycarbonyldecyl)-2,4,5-triphenylimidazole (1.95g, 45%) as an oil.

(b) 1-(10-Ethoxycarbonyldecyl)-2,4,5-triphenylimidazole (1.3g) was reacted with 2N sodium hydroxide in a method similar to Example 2 to give, after column chromatography on silica gel eluted with a dichloromethane:methanol gradient and recrystallisation from ethyl acetate/hexane, 1-(10-carboxydecyl)-2,4,5-triphenylimidazole (0.25g, 19.2%) as a cream solid, m.p. 76-78°. Found: C, 79.68%; H, 7.56%; N, 5.78%;

^C32^H36^N2°2 requires: C, 79.96%; H, 7.55; N, 5.83%. Example 9

a) 2-Methyl-4,5-diphenylimidazole (2.5g) (J. Org. Chem., 1937, 2, 328) was reacted with sodium hydride (0.62g) and ethyl 8-bromooctanoate (3.36g) in a method similar to Example 4. Chromatography on silica gel eluted with a dichloromethane:ethanol gradient gave 1-(7-ethoxycarbonylheptyl)-2-methyl-4,5-diphenylimzdazole (3.1g, 72.1%) as an oil. NMR δ (CDC1₃) 1.15 (6H, m, 3 X CH₂) , 1.25 (3H, t, CH₂CH₃) , 1.50 (4H, m, NCH₂CH₂, 0=CCH₂CH₂) , 2.23 (2H, t, CH₂C0₂), 2.50 (3H, S, CH₃) , 3.69 (2H, t, NCH₂), 4.10 (2H, q, 0=C-0CH₂) , 7.10-7.50 (10H, m, 2 x Ph) ppm

b) 1-(7-Ethoxycarbonylheptyl)-2-methyl-4,5-diphenyl- imidazole (3.0g) was reacted with 2N sodium hydroxide in a method similar to Example 2 to give, after recrystallisation from acetonitrile, l-(7-carboxyheptyl)- 2-methyl-4,5-dipheny.Λimidazole (1.19g, 42.5%) as white needles, m.p. 135-6°. Found: C, 75.37; H, 7.39; N, 7.27%; ^C24^H28^N2°2 ¹*^{9% H}2° requires: C, 75.14; H, 7.57; N, 7.30%.

Example 10

A mixture of l-(7-carboxyheptyl)-2-methyl-4,5- diphenylimidazole (0.5g), concentrated sulphuric acid (0.5ml) and absolute alcohol (50ml) was heated at reflux for 3h. The solvent was removed in vacuo, the residue dissolved in ethyl acetate (50ml) , washed with water (25ml) , dried over anhyr.rous magnesium sulphate and evaporated to dryness .. vacuo. Column chromatography on silica gel eluted with a dichloromethane:ethanol gradient gave l-(7-ethoxycarbonylheptyl)-2-methyl- ,5-diphenyl- imidazole (0.22g, 41%) as an oil. Found: C, 75.70; H, 7.88; N, 7.01%;

^C2₆ ^H ₃₂ ^N2°₂ ¹*^{7 H}2° requires: C, 75.90; H, 8.03; N, 6.89%.

Example 11

a) A mixture of 2,4,5-triphenylimidazole (11.5g), 1,7- dibromoheptane (50g) and potassium carbonate (27g) in dry butanone (250ml) was heated at reflux for 20 hours. The mixture was filtered and the filtrate evaporated to an oil. Chromatography on silica gel (hexane/ethyl acetate) and recrystallisation from hexane gave l-(7-bromoheptyl)- 2,4,5-triphenylimidazole (11.3g, 61.4%) as a colourless solid, m.p. 69-71°.

Found: C, 71.18; H, 6.22; N, 5.99; Br, 16.95%;

C ₈H₂₉BrN₂ requires: C, 71.03; H, 6.17; N, 5.92; Br, 16.88%;

b) l-(7-Bromoheptyl)-2,4,5-triphenylimidazole (7g) in dry dimethylsulphoxide (15ml) was added over 20 minutes to a mixture of sodium cyanide (0.87g) in dimethyl¬ sulphoxide (25ml) . The reaction was stirred at 40°C for 1 hour. The cooled reaction mixture was poured into water (800ml) and extracted with diethyl ether (4 x 100 ml) . The extracts were combined, washed with water, dried over anhydrous magnesium sulphate and evaporated to dryness in vacuo. Recrystallisation from dichloromethane/hexane gave l-(7-cyanoheptyl)-2,4,5-triphenylimidazole (3.7g,60%) as a white solid, m.p. 93-94°. Found: C, 82.35; H, 6.90; N, 9.96%;

^C29^H2₉ ^N ₃ ^{1% CH}2^C12 requires C, 82.43; H, 6.91; N, 9.91%.

c) A mixture of l-(7-cyanoheptyl)-2,4,5-triphenyl- imidazole (2g) , tri-n-butyl tin azide (5g) and dry tetrahydrofuran (30ml) , under nitrogen, was heated at reflux for 8 hours. Tri-n-butyl tin azide (4.9g) in dry tetrahydrofuran (5ml) was added and the reaction was hoated at reflux for 48 hours. The cooled reaction mixture was poure^d into 2N hydrochloric acid (100ml) and water (100ml) was added. The aqueous mixture was extracted with dichloromethane (2 x 50 ml) . The organic extracts were combined, washed with saturated sodium chloride solution (50ml) , dried over anhydrous magnesium sulphate and evaporated to dryness in vacuo.

Chromatography on silica gel (dichloromethane/methanol) gave 1-(7-(5-tetrazolylheptyl)-2,4,5-triphenylimidazole (0.2g, 9%) as a foam. Found: C, 74.08; H, 6.63; N, 17.30%; C₂₉H₃₀N₆. 0.5% W/N C₂H₅0H requires C, 74.14; H, 6.87; N, 17.26%.

Example 12

8-Bromooctanoic acid (22.3g) , 2-(2-methoxyethoxy)- ethanol (14.08g) and p-toluenesulphonic acid (O.lg) were added to toluene (250ml) and the resulting soution heated at reflux temperature for 16 hours. Ethyl acetate (500ml) was then added and the solution washed with aqueous K₂C0₃ solution and water, dried and evaporated. The residual oil was distilled to give 2-(2-methoxyethoxy)- ethyl 8-bromooctanoate (25.5g) , 77%) as a colourless oil, b.p. 126-128°C/0.08 mm Hg.

The above alkyl bromide (7.5g) and 2,4,5-triphenyl- imidazole (4.44g) were treated with K₂C0₃ (3.1g) in refluxing 2-butanone (60ml) for 18 hours. The solvent was evaporated and the resulting solid chromatographed on silica gel to give 2-(2-methoxyethox Methyl 8-(2,4,5- triphenylimidazol-l-yl)octanoate (l.5g, 42%) as a colourless oil.

Found: C, 75.13; H, 7.47; N, 5-18%;

C₃₄H₄₀N₂O₄ requires: C, 75.53; H, 7.46; N, 5.18%

Example 13

4,5-Triphenylimidazole (5.5g) was treated with ethyl 8-bromooctanoate (12.55g) by the method described in example 1 to give, after work-up and chromatography, ethyl 8-(4,5-diphenylimidazol-l-yl)octanoate (7.8g, 80%) as a pale yellow oil.

Found: C, 76.67; H, 7.85; N, 7.07%

^C25^H ₃₀ ^N2°2 requires: C, 76.89; H, 7.74; N, 7.17%

Example 14

Ethyl 8-(4,5-diphenylimidazole-l-yl)octanate (3.25g) was treated with sodium hydroxide as described in example 2 to give 8-(4,5-diphenylimidazol-l-yl)octanoic acid (0.6g, 20%) as colourless needles, m.p. 129.5-130°C. Found: C, 75.75; H, 7.20; N, 7.53% ^C2₃ ^H26^N2°2 °-^{1 HC1} requires: C, 75.45; H, 7.18; N, 7.65%

Example 15

4,5-Diphenylimidazole (2.85g) was treated with 2-(2-methoxyethoxy) ethyl 8-bromooctanoate (8.63g) as described in Example 12 to give 2-(2-methoxyethoxy)ethyl 8-(4,5-diphenylimidazole-l-yl)octanoate as a colourless oil (1.5g, 25%).

Found: C, 72.28; H, 7.91; N, 6.35% ^C28^H36^N2°4 requires: C, 72.38; H, 7.81; N, 6.03% Example 16

a) 2-(4-Methoxyphenyl)-4,5-diphenylimidazole (log) (J. Org. Chem. , 1964, 29, 1926-30) was reacted with sodium hydride (1.7g) and ethyl 8-bromooctanoate (9.6g) in a method similar to Example 4. Chromatography on silica gel eluted with chloroform gave l-(7-ethoxy- carbonylheptyl)2-(4-methoxyphenyl)-4,5-diphenylimidazole (12.9g, 85%) as an oil.

b) 1-(7-Ethoxycarbonylheptyl)-2-(4-methoxyphenyl)-4,5- diphenyli idazole (5g) was treated as in Example 2. Work-up and recrystallisation from ethanol gave

1-(7-carboxyheptyl)-2-(4-methoxyphenyl)-4,5-diphenyl- imidazole (3.51g, 75%) as a white solid, m.p 173-4°. Found: C, 76.23; H, 6.89; N, 5.71%;

^C ₃0^H ₃2^N2°₃ ^{+ 1% w}/^{w C}2^H5^0H requires: C, 76.64; H, 6.94; N, 5.92%;

Example 17

1-(7-Carboxyheptyl)-2-(4-methoxyphenyl)-4,5-diphenyl- imidazole (0.4g) was reacted with ethanol and concentrated sulphuric acid in a method similar to Example 10 to give, after work-up and column chromatography on silica gel eluted with a dichloromethane:ethanol gradient, 1-(7-ethoxycarbonylheptyl)-2-(4-methoxyphenyl)-4,5- diphenylimidazole (0.21g, 50%) as an oil. Found: C, 77.39; H, 7.55; N, 5.96%; ^C ₃2^H ₃₆ ^N2°₃ requires: C, 77.39; H, 7.31; N, 5.64%. Example 18

1-(7-Carboxyheptyl)-2-(4-methoxyphenyl)-4,5-diphenyl- imidazole (2.5g) was added, in portions over 40 minutes, to a solution of boron tribromide (2.17ml) in anhydrous dichloromethane (40ml) . The reaction was stirred at room temperature for 5h, cooled and water (50ml) was carefully added. The organic layer was removed and the aqueous layer was washed with dichloromethane (3 x 75ml) . The organic extracts were combined, dried over anhydrous magnesium sulphate and evaporated to dryness in vacuo. Column chromatography on silica gel eluted with a dichloromethane:methanol gradient and recrystallisation from ethanol/water and acetonitrile gave l-(7-carboxy- heptyl)-2-(4-hydroxyphenyl)-4,5-diphenylimidazole (0.49g, 20%) as a white solid, m.p. 171-172°. Further material was obtained from the mother liquors (0.79g, 33%) m.p. 167°. Found C: 76.85; H, 6.65; N, 6.20%; ^C2₉ ^H ₃₀ ^N2°3 requires: C, 76.63; H, 6.65; N, 6.16%;

Example 19

A solution of iodine (0.25g) and potassium iodide (0.48g) in water (1ml) was added to a mixture of

1-(7-carboxyheptyl)-2-(4-hydroxyphenyl)-4,5,-diphenyl- imidazole (0.2g) in 25% aqueous methylamine (1.5ml), cooled in an ice-bath. The reaction mixture was stirred at room temperature for 2h, aqueous sodium metabisulphite solution was added and stirring was continued for 0.5h. The reaction mixture was acidified to pH3 with glacial acetic acid. The resulting orange solid was collected and washed with aqueous sodium metabisulphite solution. Recrystallisation from ethanol/water gave l-(7-carboxy- heptyl)-2-(4-hydroxy-3,5-diiodophenyl)-4,5-diphenyl- imidazole (0.14g, 45%) as an off-white solid, m.p. 186°. Found: C, 49.49; H, 3.99; N, 4.36; I, 35.64%; ^C2₉ ^H2₈ ^I2^N ₂°₃ requires: C, 49.31; H. 4.00; N, 3.97; I, 35.93%.

Example 20

2-Benzyl-4,5-diphenylimidazole (3.3g) (Weiss, M, J. Am. Chem. Soc, 1952, 74, 5193-5) was reacted with ethyl 8-bromooctanoate as in Example 1. Column chromatography on silica gel eluted with a dichloro¬ methane:ethanol gradient followed by distillation at 200°C/0.1 torr to remove volatile impurities gave a yellow oil. Recrystallisation from hexane gave

2-benzyl-l-(7-ethoxycarbonylheptyl)-4,5-diphenylimidazole

(2.69g, 52.6%) as a white solid, m.p. 82-3°.

Found: C, 80.35; H, 7.58; N, 6.08%;

^C ₃2^H ₃₆ ^N2°2 requires: C, 79.96; H, 7.55; N. 5.83%.

Example 21

2-Benzyl-l-(7-ethoxyσarbonylheptyl)-4,5-diphenyl- imidazole (1.5g) was treated in a method similar to Example 2. Ethanol was removed in vacuo and the aqueous solution was acidified with 2N aqueous hydrochloric acid and extracted with dichloromethane (2 x 75ml) . The extracts were combined, dried over anhydrous magnesium sulphate and evaporated to dryness in vacuo. Recrystallisation from ethanol gave 2-benzyl-l-(7- carboxyheptyl)-4,5-diphenylimidazole (1.14 g, 81%) as a white solid, m.p. 148-9°.

Found: C, 79.56; H, 7.13; N, 6.04%;

^C3₀ ^H ₃2^N2°2 requires: C, 79.61; H, 7.13; N, 6.19%. Example 22

a) 2-(4-Hydroxyphenyl)-4,5-diphenylimidazole (5g) (J. Org. Chem., 1964, 29, 1926) was reacted with 8-bromooctane (6.2g) in a method similar to Example l.

Work-up and recrystallisation from ethanol and water gave 2-(4-octyloxvphenyl₎-4,5-diphenylimidazole (₄.29g, ₆₃%₎ as a white solid, m.p. 178°. Found: C, 82.317 H, 7.66; N, 6.73%; C₂₉H₃₂N₂0 requires C, 82.04; H, 7.60; N, 6.60%.

b) 2-(4-0ctyloxyphenyl)-4,5-diphenylimidazole (2.5g) was reacted with ethyl 8-bromooctanoate (2.96g) in a method similar to Example l. Column chromatography on silica gel eluted with a hexane:ethyl acetate gradient gave 1-(7-ethoxycarbonylheptyl)-2-[4-octyloxyphenyl]-4, 5-diphenylimidazole (3.48g, 94%) as an oil. NMR δ (CDC1₃); 0.8-1.5 (23 H, m, 10 X CH2, CH3) , 1.8 (2 H, q, 0CH2CH2), 2.2 (2H, t, CH₂(C=0) , 3.85 (2H, t, NCH₂), 4.05 (4H, m, CH₂0C=0, C0CH2) , 6.95-7.6 (14H, m, ArH) ppm.

c) 1-(7-Ethoxycarbonylheptyl)-2-[4-octyloxyphenyl]-4, 5-diphenylimidazole (3.2g) was reacted with 2N sodium hydroxide in a method similar to Example 1. Column chromatography on silica gel eluted with a dichloro¬ methane:methanol gradient and recrystallisation from acetonitrile gave l-(7-carboxyheptyl)-2-[4-octyloxy- phenyl]-4,5-diphenylimidazole (1.7g, 58.6%) as a white solid, m.p. 114-115°.

Found: C, 78.61; H, 8.23; N, 4.96%;

^C37^H46^N2°₃ requires: C, 78.41; H, 8.18; N, 4.94%. Example 23

a) A mixture of 4,5-diphenyl-2-imidazolethiol (2.5g), 8-bromooctane (3.8g), anhydrous potassium carbonate (13.7g) and dry butanone (60ml) was stirred at reflux for 2h. The cooled reaction mixture was filtered to remove solid and the filtrate was evaporated to dryness. The residue was mixed with hexane and the resulting precipitate was collected by filtration. Recrystallisation from ethanol and water gave

2-octylthio-4,5-diphenylimidazole (1.9g, 53%) as a white solid, m.p. 133-4°.

Found: C, 76.15; H, 7.82; N, 7.74, S, 9.23%;

C₂₃H₂₈N₂S requires: C, 75.78; H, 7.74; N, 7.68; S, 8.80%.

b) 2-0σtylthio-4,5-diphenylimidazole (1.7g) was reacted with ethyl 8-bromαctanoate in a method similar to Example 1 to give, after chromatography on silica gel eluted with a hexane:dichloromethane gradient, l-(7-ethoxycarbonyl- heptyl)-2-octylthio-4, 5-diphenylimidazole (2.19g, 87.6%) as an oil.

NMR (CDC1₃) 0.89 (3H, t, CH2CH3) , 1.0-1.8 (20H, m, 10X(CH₂)), 2.2 (2H, t, CH₂=0) , 3.2 (2H, t, SCH2) , 3.78 (2H, t, NCH2), 4.1 (2H, q, CH₂0C=0) , 7.0-7.5 (10H, m, 2 x Ph) ppm.

c) 1-(7-Ethoxycarbonylheptyl)-2-octylthio-4 ,5-diphenylim idazole (lg) was reacted with 2N sodium hydroxide in a method similar to Example 2 to give, after chromatography on silica gel eluted with a dichloromethane:methanol gradient, l-(7-carboxyheptyl)-2 octylthio-4,5-diphenyl- imidazole (0.47g, 49%) as an oil.

Found: C, 73.56; H, 8.59; N, 5.60; S, 6.47%;

C₃₁H₄₂N₂0₂S requires: C, 73.47; H, 8.35; N, 5.53; S, 6.33%. Example 24

4,5-Bis(4-methoxyphenyl)imidazole (l.8g) (J. Med. Chem. , 1974, 17, 1182-8) and ethyl 8-bromooctanoate (3.2g) were reacted in a method similar to Example 1. Column chromatography on silica gel eluted with a dichloromethane:ethanol gradient gave l-(7-ethoxycarbonyl- heptyl)-4,5-bis(4-methoxyphenyl)imidazole (2.42g, 83%) as an oil. Found: C, 72.30; H, 7.72; N, 6.21%;

^C27^H ₃4^N2°4 requires: C, 71.97; H, 7.61; N, 6.22%.

Example 25

1-(7-Ethoxycarbonylheptyl)-4,5-bis(4-methoxyphenyl)- imidazole (0.58g) was reacted with 2N sodium hydroxide in a method similar to Example 2. Recrystallisations from ethanol and water gave l-(7-carboxyheptyl)-4,5-bis(4- methoxyphenyl)imidazole (0.25g, 46%) as a white solid, m.p. 142-143°.

Found: C, 71.17; H, 7.20; H, 6.67%;

^C2₅ ^H ₃₀ ^N2°₄ requires: C, 71.07; H, 7.16; N, 6.63%.

Example 26

a) Boron tribromide (1.3ml) was added to a solution of 1-(7-ethoxycarbonylheptyl)-4,5-bis(4-methoxyphenyl)- imidazole (1.25g) in dry dichloromethane (30ml) . The reaction was stirred at room temperature for 4h, cooled and water (20ml) was carefully added. The resulting purple precipitate was collected and column chromatography on silica gel eluted with a dichloromethane:methanol gradient, followed by recrystallisation from ethanol and water gave 1-(7-ethoxycarbonylheptyl)-4,5-bis(4- hydroxyphenyl)imidazole as a white solid (0.58g, 50%), m.p. 186-187°.

b) The above ester (0.5g) was reacted with 2N sodium hydroxide in a method similar to Example 2.

Recrystallisations from ethanol and water gave 1-(7-carboxyheptyl)-4,5-bis(4-hydroxyphenyl)imidazole (0.16g, 34%) as a white solid, m.p. 203-204°. Found: C, 69.71; H, 6.70; N, 6.99%; ^C2₃ ^H2₆ ^N2°4 requires: C, 70.03; H, 6.64; N, 7.10%.

Example 27

a) 4,5-Bis(2-chlorophenyl)imidazole (1.2g) (Chem. Ber., 1959, 92, 338-343) and ethyl 8-bromooctanoate (2.1g) were reacted in a method similar to Example l. Column chromatography on silica gel eluted with a dichloro¬ methane:ethanol gradient gave 4,5-bis(2-chlorophenyl)-1- (7-ethoxycarbonylheptyl)imidazole (0.45g, 23.7%) as an oil.

NMR (CDC1₃) 1.0-1.8(11H, m, 4 X CH2, CH3) , 2.2(2H, t, CH₂C=0) , 3.8 (2H, m, N-CH2), 4.1(2H, q, CH₂0C=0) , 7.1-7.45 (8H, m, ArH) , 7.69 (1H, s, N=CH) ppm

) 4,5-Bis(2-chlorophenyl)-l-(7-ethoxycarbonylheptyl)- imidazole (0.4g) was reacted with 2N sodium hydroxide in a method similar to Example 2. Work-up and chromatography on silica gel eluted with a dichloromethane:methanol gradient followed by recrystallisation from dichloro- methane and hexane gave l-(7-carboxyheptyl)-4,5-bis-

(2-chlorophenyl)imidazole (0.25g, 67%) as a white solid, m.p. 145-6°.

Found: C, 64.20; H, 5.61; N. 6.64; Cl, 16.62%; C₂₃H₂ C1₂N₂0₂ requires: C, 64.04; H, 5.61; N, 6.49; Cl, 16.44%. Example 28

a) 4,5-Bis(2-chlorophenyl)-2-phenylimidazole (1.7g) (J. Org. Chem., 1971, 36, 2262) was reacted with ethyl 8-bromooctanoate in a method similar to Example 1. Column chromatography on silica gel eluted with a dichloromethane:ethanol gradient gave 4,5-bis(2-chloro- phenyl)-1-(7-ethoxycarbonylheptyl)-2-phenylimidazole (l.94g, 77.6%) as an oil. NMR δ (CDC1₃) 0.8-1.5 (10H, m, 5 x CH2) , 2.18(2H, t, CH₂C=0) , 3.85 (2H, m, NCH2) , 4.1 (2H, q, CH₂0C=0) , 7.1-7.5 (13H, m, ArH) ppm.

b) 4,5-Bis(2-chlorophenyl)-1-(7-ethoxycarbonylheptyl)- 2-phenylimidazole (1.9g) was reacted with 2N sodium hydroxide in a method similar to Example 2. The aqueous reaction mixture was evaporated to remove ethanol and acidified to pH5 with 2N aqueous hydrochloric acid. The resulting white solid was collected and recrystallisation from ethanol gave l-(7-carboxyheptyl)-4,5-bis(2-chloro- phenyl)-2-phenylimidazole (1.31g, 73%) as a white solid, m.p. 198°.

Found: C, 68.53; H, 5.60; N, 5.37; Cl, 14.79%; ^C2₉ ^H2₈ ^C12^N2°2 °-²% W/w C₂H₅0H requires: C, 68.31; H, 5.70; N, 5.40, Cl, 13.69%.

Example 29

a) 4,5-Bis(4-methoxyphenyl)-2-phenylimidazole (7g) (J. Med. Chem., 1974, 17, 1182-8) and ethyl 8-bromo- octanoate (9.9g) were reacted in a method similar to Example 1. Column chromatography on silica gel eluted with a hexane:ethyl acetate gradient gave l-(7-ethoxy- carbonylheptyl)-4,5-bis(4-methoxyphenyl)-2-phenyl- imidazole (10.3g, 100%) as an oil. NMR δ (CDC1₃) 0.8-1.5 (13H, m, 5xCH₂, CH₃) , 2.18 (2H, t, CH₂=0) , 3.75 (3H, s, OCH₃) , 3.88 (5H, m, NCH₂, OCH₃), 4.1 (2H, q, CH₂OC=0) , 6.7-7.7 (13H, m, ArH) ppm.

b) 1-(7-Ethoxycarbonylheptyl)-4,5-bis(4-methoxypheny1)- 2-phenylimidazole (lOg) was reacted with 2N sodium hydroxide in a method similar to Example 2. The aqueous reaction mixture was evaporated to dryness in vacuo and the residue was mixed with ethanol (150ml) and insoluble material was filtered off. The filtrate was evaporated to dryness and the residue was purified by column chromatography on silica gel eluted with a dichloro¬ methane:methanol gradient. Further purification on Amberlite resin IRA-400 eluted with a methanol:water to methanol:2N HCl gradient and recrystallisation from ethanol gave l-(7-carboxyheptyl)-4,5-bis(4-methoxy- phenyl)-2-phenylimidazole (2.01g, 21%) as a white solid, m.p. 149-150°. Found: C, 74.50; H, 6.75; N, 5.69%. ₃1^H ₃4^N2°₄ °-^{5% w} w C₂H₅0H requires: C, 74.56; H, 6.90; N, 5.59%.

Example 30

Boron tribro ide (0.7ml) was added to a suspension of 1-(7-carboxyheptyl)-4,5-bis(4-methoxypheny1)-2- phenylimidazole (0.7g) in anhydrous dichloromethane (20ml) and the reaction was stirred at room temperature for lh. Boron tribromide (0.3ml) was added and the reaction was stirred at reflux for 2h and at room temperature for 2Oh. Water was carefully added to the cooled reaction mixture and the resulting yellow precipitate was collected. Column chromatography on silica gel eluted with a dichloromethane:methanol gradient and recrystallisation from ethanol and water gave 1-(7-carboxyheptyl)- 4,5-bis(4-hydroxyphenyl)-2- phenylimidazole (0.44g, 67%) as a cream solid, m.p 135-7° Found C, 73.97; H, 6.38; N, 5.98%;

^C2₉ ^H ₃₀ ^N2°4 requires: C, 74.02; H, 6.42; N, 5.95%.

Example 31

4,5-Di-(4-bromophenyl)imidazole (2.13g) was treated with ethyl 8-bromooctanoate (2g) and K₂C0₃ (0.5g) in 2-butanone as described in Example 1 to give ethyl 8-(4,5-di-(4-bromophenyl)imidazol-l-yl)- octanoate (2.2g, 52%) as a pale yellow oil. Found: C, 55.13; H, 5.19; N, 5.18; Br; 28.76%

C₂₈H ₈Br₂N₂0₂ requires: C, 54.76; H, 5.15; N, 5.11; Br, 29.15%

Example 32

a) 2-Heptyl-4,5-diphenylimidazole (lg) was reacted with ethyl 8-bromooctanoate (1.6g) in a method similar to Example 1 with a reaction time of 48 hours. Chromatography on silica gel (hexane/ethyl acetate) gave 1-(7-ethoxycarbonylheptyl)-2-heptyl-4,5-diphenylimidazole (1.3g, 87%) as an oil. Found: C, 78.98; H, 9.22; N, 5.76%; ^C32^H44^N2°2 requires: C, 78.64; H, 9.08; N, 5.73%;

b) l-(7-Ethoxycarbonylheptyl)-2-heptyl-4,5-diphenyl- imidazole (lg) was reacted with sodium hydroxide in a method similar to Example 2 to give, after column chromatography on silica gel (dichloromethane/methanol) and recrystallisation from hexane, l-(7-carboxyheptyl)-2- heptyl-4,5-diphenylimidazole (0.26g, 28%) as a white solid, m.p. 75-6°.

Found: C, 78.04; H, 8.85; N, 6.10%;

^C ₃₀ ^H4₀ ^N2°2 requires: C, 78.22; H, 8.75; N, 6.08%;

Example 33

To a solution of sodium (0.17g) in dry methanol (10ml) was added ercaptoacetic acid (0.3g followed by l-(6-bromohexyl)-2,4,5-triphenylimidazole (l.38g). The suspension was stirred at room temperature for 2 hours then at reflux temperature for 4 hours. The solvent was evaporated and the residue was dissolved in water and acidified to pH 4 with dilute hydrochloric acid. The precipitated oil was taken up in dichloromethane, washed with water, dried over magnesium sulphate and evaporated to an oil which was chromatographed on silica gel (dichloromethane/methanol) giving, after recrystallisation from ethanol, 6-(2,4,5-triphenylimidazol-l-yl)hexylthio- acetic acid (0.86 g, 61%) as a colourless crystalline solid, m.p. 158-9°C.

Found: C, 74.14; H, 6.43; N, 5.77; S, 6.91% ^C ₂₉ ^H ₃₀ ^N ₂°2^S requires: C, 74.01; H, 6.43; N, 5.95; S, 6.81%

Example 34

a) A mixture of 2,4,5-triphenylimidazole (20g) , dibromopentane (62g) and potassium carbonate (18g) in dry butanone (200ml) was heated at reflux temperature for 24 hours. The mixture was filtered and the filtrate evaporated to an oil. This was washed with hexane then chromatographed on silica gel (hexane/ethyl acetate) to give l-(5-bromopentyl)-2,4,5-triphenylimidazole (7.9g, 27%) as a pale yellow oil. NMR δ (CDC1₃) 1.0-1.6 (3H, m, 3 X CH₂) , 3.1 (2H, t, CH₂Br) , 3.9 (2H, t, CH₂N) , 7.1-7.7 (15H, m, 3 X Ph) pp .

b) Mercaptoacetic acid (0.3g) and l-(5-bromopentyl)-

2,4,5-triphenylimidazole (1.34g) were reacted in a method similar to example 34 giving, after recrystallisation from isopropanol, 5-(2,4,5-triphenylimidazol-l-yl)pentyl- thioacetic acid (0.52g, 38%) as a colourless crystalline solid, m.p. 166-9°C.

Found: C, 72.98; H, 6.07; N, 5.87; S, 6.90%

^C2₈ ^H28^N2°2^{S +} ■% isopropanol + 0.5% water requires: C, 73.15; H, 6.28; N, 6.04; S, 6.92%

Example 35

A solution of 2,4,5-triphenylimidazole (1.07g) in dimethylformamide (20ml) was treated with sodium hydride 50% in oil (0.17g) and methyl 7-bromohept-5-ynoate (0.95g). The solution was stirred for 18 hours when the solvent was removed under reduced pressure and the residue was chromatographed on silica gel eluted with chloroform-hexane to give a clear oil which was dissolved in methanol (20ml) and treated with 10% potassium hydroxide solution (10ml) for 2 hours. The methanol was removed under reduced pressure and the remaining aqueous was acidified (pH 3) and filtered. The filtrate was extracted with chloroform (3 x 50ml) . The chloroform extracts were dried over magnesium sulphate, filtered and the solvent removed to give a solid which was recrystallised from acetonitrile to give 7-(1,2,4- triphenylimidazolyl)-hept-5-ynoic acid as white prisms, m.p. 144-145°C.

Found: C, 79.99; H, 5.81; N, 6.40% (C₂₈H₂₄N₂0₂) ; Requires: C, 79.97; H, 5.75; N, 6.66% Example 36

A mixture of 2,4,5-triphenylimidazole (4.13g), ethyl 9-bromo-2,2-dimethylnonanoate (10.95σ), potassium carbonate (lOg) and 2-butanone was stirred at reflux for 48 hours. The mixture was filtered, solvent removed under reduced pressure and the residue was chromatographed on silica gel eluted with chloroform to give a clear oil which was dissolved in dimethyl sulphoxide (30ml) and treated with potassium hydroxide (3g) . The mixture was stirred at 40°C for 24 hours when the solvent was removed under reduced pressure. Water (50ml) was added, the pH of the solution was ajusted to 4 and the aqueous was extracted with chloroform (3 x 50ml) . The chloroform extracts were dried over magnesium sulphate, filtered and the solvent removed to give a solid which was recrystallised from acetonitrile to give 9-(l,2,4-tri- phenylimidazolyl)-2,2-dimethylnonanoic acid as a white crystalline solid, m.p. 119-120°C. Found: C, 79.85; H, 7.64; N, 6.23% (C₃₂H₃₆N₂0₂) Requires: C, 79.96; H, 5.54; N, 5.82%

Example 37

a) A mixture of 1,4 dibromobutane (50ml), methyl

4-hydroxybenzoate (15.2g, 0.1 mole), potassium carbonate (40g) in 2-butanone (500ml) was refluxed for 24 hours. The mixture was filtered, solvent removed and the residue was chromatographed on silica gel eluted with chloroform/ petrol and recrystallised from pentane to give methyl 4- 4-bromobutyloxy)benzoate (19.26g) .

b) A mixture of 2,4,5-triphenylimidazole (5.93g), methyl 4-(4-bromobutyloxy)benzoate (3.81g), potassium carbonate (25g) and 2-butanone (250ml) was stirred at reflux for 36 hours. The mixture was filtered, solvent removed under reduced pressure and the residue was chromatographed on silica gel eluted with chloroform and recrystallised from methanol to give 4-[4-(2,4,5- triphenylimidazolyl)butyloxy]benzoate as a white crystalline solid (5.38g), m.p. 145-146°C. Found: C, 79.16; H, 6.15; N, 6.03% (C₃₃H₃₀N₂O₃) Requires: C, 78.86; H, 6.01; N, 5.57%

c) Methyl 4-[4-(2,4,5 triphenylimidazolyl]butyloxy)- benzoate (1.5g) was dissolved in methanol (50ml) and treated with 10% potassium hydroxide solution (15ml) for 0.5 hours. The methanol was removed under reduced pressure and the remaining aqueous was acidified (pH4) and the precipitate was collected by filtration and recrystallised from methanol to give 4-[4-(2,4,5- triphenylimidazolyl)butyloxy]benzoic acid (1.3g) as white prisms m.p. 202-203°C. Found: C, 78.79; H, 5.75; N, 5.81% (C₃₂H₂₈N₂0₃) ; Requires: C, 78.66; H, 5.78; N, 5.73%

Example 38

2,4,5-Triphenyl-l-(7-bromoheptyl)imidazole (0.95g) was dissolved in hot ethanol (10ml) and a solution of sodium sulphite (0.38g) in hot water (5ml) was added. The white suspension was heated at reflux temperature for 20 hours then evaporated to dryness. The mixture was taken up in dichloromethane, filtered and the filtrate evaporated to an oil which was chromatographed on silica gel (dichloromethane/methanol) . The resulting oil was dissolved in methanol and excess ether added giving an oil which slowly solidified to give sodium 7-(2,4,5-tri- phenylimidazol-l-yl)heptanesulphonate (0.32g; 32%) as a white solid, m.p. 310°C.

Found: C, 65.98; H, 6.11; N, 5.71; S, 6.22% C₂₈H₂₉N₂Na0₃S + 2.5% H₂0 requires: C, 66.03; H, 6.02; N, 5.50; S, 6.30%

Example 39

A mixture of 2,4,5-triphenyl-l-(7-bromoheptyl)- imidazole (0.95g) and triethyl phosphite (1.66g) in xylene (5ml) was heated at reflux temperature for 20 hours. The mixture was evaporated to an oil and chromatographed on silica gel (ethyl acetate/ethanol) to give diethyl 7-(2,4,5-triphenylimidazol-l-yl)heptane- phosphonate (0.37g, 35%) as a light brown oil.

NMR δ (CDC1₃) 0.9-1.7 (18H, m, 6 X CH₂ + 2 X CH₃), 3.9 (2H, t, CH₂N) , 4.1 (4H, m, 2 X CH₂0) , 7.1-7.7 (15H, m, 3 x Ph) ppm.

Diethyl 7-(2,4,5-triphenylimidazol-l-yl)heptane- phosphonate (0.35g) was dissolved in dry chloroform, cooled to -40°C and to it was added trimethylsilyl iodide (0.66g) over 2 minutes under an atmosphere of nitrogen. The cooling bath was removed and the reaction mixture was stirred for 3 hours at room temperature then evaporated to an oil and re-evaporated from methanol and water respectively. The oil was taken up in methanol, treated with excess aqueous sodium bicarbonate, evaporated to dryness then taken up in ethanol, filtered and the filtrate evaporated to an oil. This was taken up in water, t .ltered and dilute hydro iloric acid added to pH4. The precipitated oil was washed with water, taken up in methanol and precipitated with ether to give 7-(2,4,5-triphenylimidazol-l-yl)heptanephosphonic acid (0.16g, 51%) as a light brown oil. Found: C, 68.12; H, 6.39, N, 5.60%

C₂₈H₃₁N₂0₃P +4% H₂0 requires: C, 68.03; H 6.76; N, 5.66%.

Example 40

a) A mixture of 4,5-diphenyl-2-imidazolethiol (2.66g), 2-(5-iodopentyl)-l,3-dioxalane (3g) , anhydrous potassium carbonate (7.26g) and dry 2-butanone (70ml) was heated at reflux for 4 hours. The cooled reaction mixture was filtered and the filtrate was evaporated to dryness in vacuo. The residue was stirred under hexane and the resulting white precipitate was collected by filtration. Recrystallisations from ethanol/water and dichloro¬ methane/hexane gave 2-(5-[l,3-dioxalan-2-yl]heptyl- thio)-4,5-diphenylimidazole (3.1g, 75%) as a white solid, m.p. 116-118°.

NMR δ (CDC1₃) 1.5-1.7 (8H, m, 4 x CH₂) , 3.09 (2H, t, SCH₂), 3.8-4.0 (4H, m, 0(CH₂)₂0), 4.8 (1H, t, CH) , 7.1-7.7 (10H, m, 2 x Ph) ppm.

b) 2-(5-[1,3-dioxalan-2-yl]pentylthio]-4,5-diphenyl- imidazole (3g) and ethyl 8-bromooctanoate (3.82g) were reacted in a method similar to Example 1. Distillation to remove volatile impurities and column chromatography on silica gel (dichloromethane/ethanol) gave 2-(5-[1,3- dioxalan-2-yl]heptylthio)-1-(7-ethoxycarbonylpentyl)-4,5- diphenylimidazole (3.02g, 70%) as a colourless oil. Found: C, 70.23; H, 8.09; N, 5.04; S, 5.85%; C₃₃H N₂0₄S requires: C, 70.18; H, 7.85; N, 4.96; S, 5.65%

c) 2-(5-[l,3-Dioxalan-2-yl]pentylthio)-l-(7-ethoxy- carbonylheptyl)-4,5-diphenylimidazole (7g) was reacted with 2N sodium hydroxide in a method similar to Example 2. Work-up and column chromatography on silica gel (dichloromethane/methanol) gave l- (carboxyheptyl) -2- [ 5- (1 , 3-dioxalan-2-yl]pentylthio) -4 , 5-diphenylimidazole (6.44g, 89%) as a colourless oil .

NMR δ (CDC1₃) 1.0-1.9 (18H, m, 9 X CH₂ ) , 2 . 3 (2H, t, CH₂) , 3.2 (2H, t, SCH₂ ) , 3.7-4.0 (6H, m,

0 (CH₂) ₂0, NCH₂) , 4.8 (1H, m, CH) , 7.0-7.5 (10H, m, 2 X Ph) ppm.

d) A mixture of l-(7-carboxyheptyl)-2-(5-[l,3-dioxalan- 2-yl]pentylthio)-4,5-diphenyl imidazole (2g) , tetrahydro¬ furan (100ml) , water (100ml) and concentrated hydrochloric acid (10ml) was stirred at 90°C for 1 hour. The reaction mixture was evaporated to remove tetrahydrofuran and the aqueous was extracted with diethyl ether (3 x 75ml) . The extracts were combined and washed with water (3 x 75ml) , dried over anhydrous magnesium sulphate and evaporated to dryness in vacuo. Column chromatography on silica gel (dichlor ethane/methanol) gave l-(7-carboxyheptyl)-2-(5- formylpentyl)-4,5-diphenylimidazole (0.93g, 50%) as a colourless oil.

Found: C, 70.62; H, 7.88; N, 5.32; S, 6.34%;

C_2gH₃₆N S0₃ requires: C, 70.70; H, 7.37; N, 5.39; S , 6.51%

Example 41

Phenanthrimidazole (2.18g) (J. Am. Chem. Soc, 1943, 65, 452-6) was treatt with ethyl 8-bromooctanoate (5.02g) and K₂C0₃ (2.76g) in 2-butanone (100ml) as described in Example 1 to give, after work up and chromatography, ethyl 8-(phe>nanthrimidazol-l-yl)octanoate (0.8g, 20%) as off white crystals, m.p. 99-101°C. Found: C, 77.34; H, 7.19; N, 7.04% ^C25^H2₈ ^N ₂°₂ requires: C, 77.29; H, 7.26; N, 7.21% BIOLOGIGAL DATA

METHOD FOR MEASUREMENT OF AGGREGATION OF WASHED HUMAN PLATELETS

Platelets were prepared from freshly drawn human blood. Blood was collected into acid citrate anticoagulant, centrifuged (5 min at 500g) , and the upper layer of platelet-rich plasma was removed. This platelet-rich plasma was incubated with aspirin (100μM) for 10 min at 37°C and then centrifuged (15 min at 200g) . The platelet pellet was resuspended (at approx. 1.5 x 10⁸ cells/ml) in medium containing NaCl (145mM) , KC1 (5mM) , MgCl₂ (ImM), CaCl₂ (0.2mM), Hepes (lOmM, pH 7.4 at 37°C) , glucose (lOmM) , apyrase (lOμg/ml) . Aggregation was monitored (as a change in optical density) at 37°C in a 4 channel aggregometer (PAP-4 from Biodata Corp.) . Fibrinogen (lmg/ml) and CaCl₂ (ImM) were added to aliquots of platelets that were continuously stirred. The test compound (or 0.1% DMSO vehicle) was added 2 min before the aggregatory stimulus (lμM U46619) . The extent of aggregation was assessed 4 min after addition of the stimulus, and was calculated as % of the control response in the absence of test compound. Dose-response curves were constructed for measurement of IC₅₀ values for each compound.

METHOD FOR MEASUREMENT OF K_j FOR INHIBITION OF [³H]ILOPROST BINDING TO HUMAN PLATELET MEMBRANES

Membranes were prepared from outdated platelet-rich plasma concentrates obtained from the Blood Transfusion Service. The platelets were homogenised in buffer containing Tris-Cl (5mM, pH 7.4 at 20°C) and EDTA (0.25mM), and then centrifuged (10 min at 26,000g). The membrane pellet was washed twice by homogenisation in buffer containing Tris-Cl (50mM, pH 7.4 at 20°C) and EDTA (0.25 mM) , followed by centrifugation. For measurement of [³H]iloprost binding, membranes (0.4-0.8mg) were incubated in the presence of Tris-Cl (50mM, pH 7.4 at 20°C), MgCl₂ (4mM), EDTA (40μM) , [³H]iloprost (lOnM) , DMSO (1.85%), and varying concentrations of the test compounds. For determination of non-specific binding, 20μM iloprost was included. The tubes (triplicates for each condition) were set up on ice, and then incubated for 30 min at 37°C. The incubations were terminated by rapid, filtration on Whatman GF/B filters using a Brandel Harvester. The filters were washed and then counted for radioactivity. The K^ of the test compounds for inhibition of binding of [³H]iloprost to human platelet membranes was calculated from the IC₅₀ for displacement of [³H]iloprost binding.

RESULTS

1. PLATELET AGGREGATION IC₅₀

The compounds of the Examples were found to exhibit IC₅₀ values generally in the range ^~f from: 0.03 to 17.8 μM.

2. INHIBITION OF ILOPROST BINDING : Ki

The compounds of the Examples were found to exhibit Ki (μM) values generally in the range of from: 0.25 to 110 μM.

Claims

Claims :

1. A compound of structure (I) :

in which each group Ar is the same or different and is optionally substituted phenyl or optionally substituted heteroaryl or, when both groups Ar are phenyl they can be linked by a bond; R is hydrogen, C₁_₈alkyl, C₁_₈alkoxy, SC--^alkyl, optionally substituted phenyl, phenyl C_1-4alkyl in which the phenyl group is optionally substituted, C₁_₆alkylCHO or C₁_₆alkylCH(OR¹) (OR²) in which each group R¹ and R² is C_1-4alkyl, or together form an ethane 1,2-diyl or propane 1,3-diyl group; n is 2 to 6 and m is 0 to 6;

R³, R⁴, R⁵ and R⁶ are the same or different and are each hydrogen or C₁_₄alkyl; AB is a bond, -CΞC-, -CH=CH-, S, 0, SPh or OPh; and

X is C0 H or a group hydrolysable to C0₂H,

5-tetrazolyl, S0₃H, P(0)(0R)₂, P(0)(0H)₂, or P(0) (R) (OR) in which R is hydrogen or C-_j^alkyl, or a pharmaceutically acceptable salt thereof.

2. A compound according to claim 1 in which each group Ar is phenyl, R is phenyl, R³, R⁴, R⁵ and R⁶ are all hydrogen, AB is a bond and X is C0₂H or a group hydrolysable to C0 H.

3. A compound according to claim 2 in which n+m is 6, 7 or 8.

4. A process for preparing a compound according to claim 1 which comprises:

(a) for compounds other than those in which X is 5-tetrazolyl, react., I of a compound of structure (II) :

(b) reaction of a compound of structure (III)

H

L(CR³R⁴)_nAB(CR⁵R⁶)_mX (IV)

in which R³, R⁴, R⁵, R⁶, AB, n, m and X are as described for structure (I) and L is a leaving group; or (c) reaction of a compound of structure (V) :

L'A¹B¹(CR⁵R⁶)_mX (VI)

in which A-'-B¹ is -CΞC-, S, O, SPh or OPh, R⁵, R⁶, m and X are as described for structure (I) and L' is hydrogen or a metal;

(d) for compounds in which X is 5-tetrazolyl reaction of a compound of structure II in which L is CN, with tri-n-butyl tin azide,

and optionally thereafter converting one group X into another group X, and optionally forming a salt.

5. A pharmaceutical composition comprising a compound according to claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutical carrier.

6. A compound according to claim 1 for use in therapy.