IMIDAZOLES

Abstract: Imidazole derivatives of formula (I) wherein A represents methylene or a group -CH2-A'-CH2- wherein A' represents a direct bond, linear alkanediyl, alkenediyl or alkynediyl, hydroxymethylene, or optionally substituted phenylene; R<1> and R<2> each represents hydrogen, halogen, alkyl, alkoxy, alkylthio, alkylamino, carboxy or alkoxycarbonyl; a and b are 0, 1 or 2; and Het represents a heterocyclic group containing from 5 to 7 ring atoms chosen from carbon, nitrogen, sulphur and oxygen atoms, and salts thereof are inhibitors of acyl coenzyme-A: cholesterol-O-acyl transferase useful for the treatment of conditions such as atherosclerosis, hyperlipidaemia, cholesterol ester storage disease and atheroma in vein grafts.

Description: IMIDA20LES This invention relates to therapeutically useful imidazole derivatives, to processes for their production and to pharmaceutical compositions containing them. The present invention provides a compound of general formula (I), hereinafter depicted, wherein: A represents a methylene group or a group -CH^-A'-C!^- wherein A' represents a direct bond, a linear alkanediyl, alkenediyl or alkynediyl group containing up to 14 carbon atoms, or a hydroxymethylene group, or A 1 represents a phenylene group optionally substituted by one to four substituents selected from halogen atoms, alkyl groups (optionally substituted by one or more halogen atoms), alkoxy, alkylthio, alkyla ino, carboxy and alkoxycarbonyl groups; 1 2 R and R are the same or different and each represents a hydrogen or halogen atom, an alkyl group (optionally substituted by one or more halogen atoms), or an alkoxy, alkylthio, alkylamino, carboxy or alkoxycarbonyl group; a and b arc the same or different and each represents 0, 1 or 2; and Het represents a heterocyclic group containing from 5 to 7 ring atoms chosen from carbon, nitrogen, sulphur and oxygen atoms, optionally substituted by one or two substituents independently selected from:- halogen atoms, alkyl groups (optionally substituted by one or more halogen atoms), hydroxy, amino, alkoxy, alkylthio, alkylamino, carboxy, alkoxycarbonyl and pyridyl groups, and phenyl groups foptionally substituted by one or more substituents selected from halogen atoms, alkyl groups (optionally substituted by one or more halogen atoms), and alkoxy, alkylthio, alkylamino, carboxy and alkoxycarbonyl groups3; and pharmaceutically acceptable salts thereof; wherein all alkyl groups and moieties, unless otherwise indicated, are straight- or branched-chain and contain from 1 to 5 carbon atoms; and halogen atoms, unless otherwise indicated, are fluorine, chlorine, bromine or iodine atoms; for use in the preparation of a pharmaceutical composition for the treatment of conditions which can be ameliorated by administration of an inhibitor of acyl coenzyme-A:cholesterol-0-acyl transferase such as atherosclerosis, hyperlipidae ia, cholesterol ester storage disease and athero a in vein grafts. The 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 administration of an inhibitor of acyl coenzyme-A:chol- esterol-O-acyl transferase such as atherosclerosis, hyperlipidaemia, cholesterol ester storage disease and atheroma in vein grafts, which comprises administering to the patient an effective amount of a compound of general formula (I), or a pharmaceutically acceptable salt thereof, as hereinbefore defined, to secure an improvement in the condition of the patient. The invention also provides a compound of general 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 administration of an inhibitor of acyl eoen2yme-A:chol- esterol-O-acyl transferase such as atherosclerosis, hyperlipidaemia, cholesterol ester storage disease and atheroma in vein grafts. The present invention also provides pharmaceutical formulations which comprise at least one of the compounds of general formula (I), or a pharmaceutically acceptable salt thereof, as hereinbefore defined provided that:- 1 2 when R and R are identical and each represents a fluorine, chlorine or bromine atom or a trifluoro ethyl, methoxy or methylthio group in the para-position and A represents a ethylene, 1,2-ethanediyl, 1,3-propanediyl, 2-hydroxy-l,3- propanediyl or l # 4~butanediyl group, then Het represents other than a group of general formula (VIII), as hereinafter depicted, wherein R represents hydrogen atom o a methyl group and the symbols R are identical and each represents a fluorine, chlorine or bromine atom or a trifluoro ethyl, methoxy or methylthio group in the para-position; in association with a pharmaceutically acceptable carrier or coating. . The present invention also provides new imidazole derivatives of general formula (I), and pharmaceutically acceptable salts thereof, as hereinbefore defined subject to the provisos that:- 1 2 1) when and R are identical and each represents a fluorine, chlorine or bromine atom or a trifluoromethyl, methoxy or methylthio group in the para-position and A represents a ethylene, 1,2-ethanediyl, 1,3-propanediyl, 2-hydroxy-l,3- propanediyl or 1,4-butanediyl group, then Het represents other than a group of formula (VIII), as hereinafter depicted, wherein represents a hydrogen atom or a methyl group and the symbols are identical and each represents a fluorine, chlorine or bromine atom or a trifluoromethyl, methoxy or methylthio group in the para-position; and 2) when A represents, a 1,3-propanediyl or 2-hydroxy- 1 2 1,3-propanediyl group, and both represent hydrogen atoms, and a and b both represent zero, then Het represents other than a group of formula (VIII) wherein represents a hydrogen atom and the symbols 4 both represent hydrogen atoms. The compounds of formula (I), as hereinbefore defined, are inhibitors of acyl coenzyme-Atcholesterol- O-acyl transferase (ACATjEC 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. In assays performed jjrt vitro, mierosomes (prepared from the livers of rats fed a diet supplemented with 0.5%w/w cholesterol and 0. 5%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 (in μg/ml) as shown in Table 1. The degree of ACAT inhibition produced is shown in Table 1. In in vivo tests, using rats fed on a similar diet to that above and further supplemented by the indicated amount (%w/w) of test compound, compounds according to the invention inhibited increases in plasma cholesterol level, measured after 3 days, relative to control animals fed on the cholesterol supplemented diet without the drug, as shown in Table 1. Compound A B C D £ F 6 ' H I J K L M N O P C R S T Compounds within the scope of general formula (I), wherein A represents a methylene, 1,2-ethanediyl, 1,3-propanediyl, 2-hydroxy-l,3-propanediyl or 1 2 1,4-butanediyl group, and R are identical and each represents a fluorine, chlorine or bromine atom or a trifluoromethyl, methoxy or methylthio group in the para-position, a and b are the same or different and each represents 0, 1 or 2, and Het represents a group of general formula (VIII), as hereinafter depicted, wherein represents a hydrogen atom or a methyl group And the symbols R are identical and each represents a fluorine, chlorine or bromine atom or a trifluoromethyl, methoxy or methylthio group in the para-position and their pharmaceutically acceptable salts, alone and in association with pharmaceutically acceptable carriers or coatings, have been disclosed in United States Patent Specification No. 4188397. However, in that specification, those compounds and their pharmaceutical compositions are described as regulating cell-mediated immunity and having anti- arthritic activity. Nowhere in that specification is there any suggestion that the compounds or their pharmaceutical compositions could be useful as inhibitors of acyl coenzyme-Ateholesterol-O-acyl transferase or in the treatment of conditions such as atherosclerosis, hyperlipidaemia, cholesterol ester storage disease or atheroma in vein grafts. Compounds within the scope of general formula (I), wherein A represents a 1,3-propanediyl or 1 2 2-hydroxy-l,3-propanediyl group, R* and R both represent hydrogen atoms, a and b both represent zero and Het represents a group of formula (VIII) wherein represents a hydrogen atom and the symbols both represent hydrogen atoms, have been disclosed by Bagry et al., Dopovidi AN URSR, (9), 801-804, 1975. However, in that paper, no biological activity nor utility of those compounds is described, nor any pharmaceutically acceptable composition, and nowhere in that paper is there any suggestion that the compounds could be useful as inhibitors of acyl coenzyme-A:chol- esterol-O-acyl transferase or in the treatment of conditions such as atherosclerosis, hyperlipidaemia, cholesterol ester storage disease or atheroma in vein grafts. Thus, the utilities disclosed in the present specification are entirely unexpected. Especially important features of the present invention are, or involve, compounds of formula (I) wherein at least one of the symbols has a value selected from the following:- (i) A represents a group -CH^-A'-CH^- wherein A' represents a direct bond, a linear alkanediyl. alkenediyl or alkynediyl group containing up to 7 carbon atoms (more especially a methylene group or a linear alkanediyl group containing 2, 3, 4 or 7 carbon atoms or a vinylene or ethynylene group) or a hydroxymethylene group, or a substituted or, more especially, unsubstituted phenylene group; 1 2 (ii) R and are the same or different and each represents a hydrogen or halogen atom, or an alkyl or alkoxy group, more especially a hydrogen atom, or a fluorine atom or a methyl or methoxy group, preferably in the -position; (iii) Het represents an optionally substituted 5- or 6-membered heterocyclic group containing up to 4 nitrogen atoms, for example an optionally substituted pyrimidinyl (preferably ρyrimidin-2-yl), pyridyl (preferably pyrid-2-yl or ρyrid-4-yl), i idazolyl (preferably imidazol-2-yl), tria2olyl (preferably l,2,4-triazol-3-yl) or tetra∑olyl (preferably tetra∑ol-5-yl) group. Preferred substituents on the group Het are alkyl (preferably methyl), amino, pyridyl (e.g. pyrid-2-yl), and optionally substituted phenyl groups; the other symbols being as hereinbefore defined, and their pharmaceutically acceptable salts. Preferred salts are acid addition salts, such as, for example, the hydrochlorides and maleates. Important compounds encompassed by the various aspects of the invention include: A 2-[3-(Pyrimidin-2-ylthio)propylthio3-4,5-di- phenylimidazole B 2-[3-(Pyrid-4-ylthio)propylthio]-4,5-diρhenyl- imidazole C 2-[3-(l-Methylimidazol-2-ylthio)propylthio]- 4,5-diphenylimidazole D 2-[3-(l-Methylimidazol-2-ylthio)propylthio]- 4,5-diphenylimidazole dihydrochloride E 1,2-Bis(4,5-diphenylimidazolτ2-ylthio)ethane F 1,3-Bis(4,5-diphenylimidazol-2-ylthio)propane G 2-[3-(4,6-Dimethylpyrimidin-2-ylthioJpropyl- thio]-4,5-diphenylimidazole H 2-[3-(l-Methylimidazol-2-ylsulphonyl)propyl- thio3-4,5-diphenylimidazole I 2-[3-(4-Methyl-l,2,4-triazol-3-ylthio)propyl- thio3-4,5-diphenylimidazole J 2-[3-(1-Methyltetrazol-5-ylthio)propylthio3- 4,5-diphenylimidazole K l-(4,5-Diphenylimidazol-2-ylthio)-3-[(4,5- dipyrid-2-yl)imidazol-2-ylthio3propane dihydrochloride L 2-[3-(l-Methyltetrazol-5-ylsulphonyl)propyl- thio3-4,5-diphenylimidazole M 2-[3-(Imidazol-2-ylthio)propylthio3-4 ,5- diphenylimidazole N 2-[4-(l-Methylimidazol-2-ylthio)butylthio3-4,5- diphenylimidazole 0 2-[4-(l-Methylimidazol-2-ylsulphonyl)butyl- sulphonyl]-4,5-diphenyliraidazole P l,4-Bis(4,5-diphenylimidazol-2-ylthio)butane Q E-l,4-Bis(4,5-diphenylimidazol-2-ylthio)- but-2-ene R 2-[6-(l-Methylimidazol-2-ylthio)hexylthio3-4,5- diphenylimidazole S 1,9-Bis(4,5-diphenylimidazol-2-ylthio)nonane T 2-[9-(l-Methylimidazol-2-γlthio)nonylthio3-4,5- diphenylimidazole AA 1,2-bis( ,5-diphenylimidazol-2-ylthiomethyl)- benzene AB 1,3-bis(4,5-diphenyliraidazol-2-ylthiomethyl)- benzene AC 1,4-bis(4,5-diphenylimidazol-2-ylthiomethyl)- benzene AD 1,3-bis(4,5-diphenylimidazol-2-ylthio)propan- 2-ol AE 4,5-diphenyl-2-[3-(l-raethylimidazol-2-ylthio)-2- hydroxypropylthio3imidazole BA 4,5-diphenyl-2-[3-(l-methylimidazol-2-γlthio)- propylthio3imidazole dimaleate BB 4,5-Diphenyl-2-[3-(3-amino-l,2,4-triazol-5- ylthio)propylthio3imidazole BC 4,5-Diphenyl-2-[3-(pyrid-2-ylthio)propylthio3- imidazole BD E-4,5-Diphenyl-2-[4-(l-methylimidazol-2-ylthio)- but-2-enylthio imidazole BE 4,5-Diphenyl-2-[3-(pyrimidin-2-ylsulphonyl)- propylthio]imidazole BF 4,5-Diphenyl-2-[4-(pyrimidin-2-ylsulphonyl)- butylthio3imidazole BG 4,5-Diphenyl-2-[3-(pyrid-2-ylsulphinyl)propyl- thio imidazole BH 4,5-Diphenyl-2-[4-(pyrimidin-2-ylthio)butyl- thio3imidazole BI 1,6-Bis( ,5-diphenylimidazol-2-ylthio)hexane„ BJ 4,5-Bis(4-methylphenyl)-2-[3-(1-methylimidazol- 2-ylthio)propylthio3imidazole BK 4,5-Bis(4-methoxyphenyl)-2-[3-(pyrimidin-2-yl- sulphonyl)propylthio]imidazole BL 4,5-Diphenyl-2- [4-(imidazol-2-ylthio)butylthio]■ imidazole BM 4,5-Diphenyl-2-[3-(pyrid-4-ylsulphonyl)propyl¬ thio]imidazole BN 4,5-Diphenyl-2-[3-(pyrid-2-ylεulphonyl)propyl¬ thio3imidazole BO 4,5-Diphenyl-2-[4-(pyrid-2-ylthio)butylthio3- imidazole BP 1,5-Bis(4,5-diphenylimidazol-2-ylthioJpentane BQ 1,4-Bis(4,5-diphenylimidazol-2-ylthio)but-2-yne BR 4,5-Diphenyl-2-[4-(l-methylimidazol-2-ylthio)- but-2-ynylthio]imidazole BS ,5-Bis(4-fluorophenyl)-2-[3-(1-methylimidazol- 2-ylthio)propylthio]imidazole BT 4,5-Bis(4-methoxyphenyl)-2-[4-(pyrimidin-2-yl- εulphonyl)butylthio3imidazole BU 4,5-Diphenyl-2-[4-(pyrid-2-ylsulphonyl)butyl- thio]imidazole BV 4,5-Diphenyl-2-[4-(pyrid-2-ylsulphinyl)butyl- thio3imidazole BW 4,5-Diρhenyl-2-{3-[4(5)-methylimidazol-2-yl- thio]propylthio)imidazole BX 4,5-Diphenyl-2-[5-(imidazol-2-ylthio)pentyl- thio]imidazole BY 4,5-Diphenyl-2-[3-(imidazol-2-ylthio)propyl- thio3imidazole dihydrochloride BZ 4,5-Diphenyl-2-[3-(imidazol-2-ylthio)propyl- thio3imidazole di aleate CA Z-l,4-Bis(4,5-diphenylimidazol-2-ylthio)- but-2-ene CB -4,5-Diphenyl-2-[4-(pyrid-2-ylsulρhonyl)butyl- thio3imidazole hydrochloride CC 4 ,5-Diphenyl-2-[ 4- (imidazol-2-ylsulphonyl)butyl- thio3imidazole. The letters A to CC are allocated to compounds for easy reference throughout this specification. Compounds of formula (I) can be prepared by the application or adaptation of known methods, by which is- meant methods used heretofore or described in the literature. . Thus, according to a feature of the invention, compounds of general formula (I), wherein A, R 1, R2, b and Het are as hereinbefore defined and a represents zero, are prepared by reacting a salt of general formula (II), as hereinafter depicted, wherein and 2 R are as hereinbefore defined and M represents an alkali metal, preferably sodium or potassium, atom, with a compound of formula: 2 1 -A-S(0) b -Het (III) wherein A, b and Het are as hereinbefore defined and 2 represents a chlorine, bromine, or iodine atom, or an alkyl- or aryl-sulphonyloxy group, for example a methanesulphonyloxy or 4-toluenesulphonyloxy group. According to a further feature of the invention, 1 2 compounds of formula (I), wherein A, R , R , a and Het are as hereinbefore defined and b represents zero, are prepared by reacting a salt of formula: Het-S " M + (V) wherein Het and M are as hereinbefore defined, with a compound of general formula (IV), hereinafter depicted, 1 2 wherein A, R , R , and a are as hereinbefore defined and Z represents a chlorine, bromine, or iodine atom, or an alkyl- or aryl-sulphonyloxy group, for example a methanesulphonyloxy or 4-toluenesulphonyloxy group. According to a further feature of the invention, compounds of formula (I), wherein A, R 1 and 2 are as hereinbefore defined, a and b are both zero and Het represents a substituted or unsubstituted 4,5-diphenyl- imidazol-2-yl group identical to that at the other end of the. molecule, [i.e. a compound of general formula (VI), hereinafter depicted, wherein A, R 1 and 2 are as hereinbefore defined], are prepared by reacting a salt of formula (II) with a compound of formula: Z^A-Z 2 (VII) 1 2 wherein A, Z and Z are as hereinbefore defined. According to a further feature of the invention, compounds of formula (I), wherein A, R 1, 2 and.Het are as hereinbefore defined and a and b are both zero, are prepared by reacting a salt of formula (II) and a salt of formula (V) with a compound of formula (VII) wherein the various symbols are as hereinbefore defined. Each of the above reactions between compounds of formulae (II) and (III), (V) and (IV), (II) and (VII), and (II), (V) and (VII) may be performed in an inert solvent, such as dimethylformamide or tetrahydrofuran, at temperatures between room temperature and the reflux temperature of the reaction mixture. According to a further feature of the present invention, compounds of general formula (I) are prepared by the interconversion of other compounds of general formula (I). For example, compounds containing alkoxycarbonyl groups can be prepared by the alkylation of compounds containing carboxy groups by the application or adaptation of known methods of alkylation, and compounds containing carboxy groups can be prepared by the hydrolysis of compounds containing alkoxycarbonyl groups by the application or adaptation of known methods of hydrolysis. According to a further feature of the invention, compounds of formula (I), wherein A, R 1, R2 and Het are as hereinbefore defined and at least one of a and b represents 1 or 2, are prepared by the oxidation of a 1 2 compound of formula (I), wherein A, R , R and Het are as hereinbefore defined and a and/or b is less than in the desired product. The oxidation may be performed by using a conventional oxidant, such as a percarboxylie- acid (e.g. m-chloroperbenzoic acid), in an inert solvent, such as dichloro ethane, at or below room temperature. By the term "pharmaceutically acceptable salts" as used in this specification is meant salts the anions or cations of which are relatively innocuous to the animal organism when used in therapeutic doses so that the beneficial pharmaceutical properties of the parent compounds of general formula (I) capable of forming salts are not vitiated by side-effects ascribable to those anions or cations. Suitable acid addition salts for use in pharmaceuticals may be selected from salts derived from inorganic acids, for example hydrochlorides, hydrobromides, phosphates, sulphates and nitrates, and organic acids, for example oxalates, lactates, tartrates, acetates, salicylates, citrates, propionates, succinates, fumarates, maleates, methylene-bis-β-hydroxynaphthoates, gentisates and di-£-toluoyltartrates. Suitable salts with bases include alkali metal (e.g. sodium and potassium), alkaline earth metal (e.g. calcium and magnesium), ammonium and amine (e.g. diethanolamine, triethanolamine, octylamine, morpholine and dioctylmethylamine) salts. According to a further feature of the invention, salts of compounds of formula (I) are prepared by reaction of the parent compounds of formula (I) with the appropriate acid or base, by the application or adaptation of known methods. As well as being useful in themselves as active compounds, salts of compounds of formula (Z) are useful for the purposes of purification of the parent compounds of formula (I), for example by exploitation of the solubility differences between the salts and the parent compounds, by techniques well known to those skilled in the art. The parent compounds of formula (I) can be regenerated from their salts by the application or adaptation of known methods. For example, parent compounds of general formula (I) can be regenerated from their acid addition salts by treatment with an alkali, e.g. aqueous sodium bicarbonate solution or aqueous ammonia solution. Parent compounds of general formula (I) can be regenerated from their salts with bases by treatment with an acid, e.g. dilute hydrochloric acid. In this specification reference to compounds of formula (I) is intended to include reference to their pharmaceutically acceptable salts, where the context so permits. The starting materials and intermediates can be prepared by the application or adaptation of known methods. Thus, compounds of formulae (III) and (IV), wherein A, R 1 , R 2 , Z 1 , Z 2 and Het are as hereinbefore defined and a or b represents zero, can be made by the reaction of salts of formulae (II) or (V), wherein R 1 , 2 R , Het and M are as hereinbefore defined, with compounds of general formula (VII), as hereinbefore 1 2 defined, Z A and Z preferably being different, by the application or adaptation of conditions similar to those described above in respect of the reactions between compounds of formulae (II) and (III), (V) and (IV), and (II) and (VII), such that only one of Z 1 and 2 is displaced. Compounds of formulae (III) or (IV), wherein A, 1 R , R , Z , Z and Het are as hereinbefore defined and a or b represents zero, can be oxidised to the corresponding compounds, wherein a or b is greater than in the starting material, by the application or adaptation of conditions similar to those described above in respect of the oxidation of compounds of formula (I). Compounds of formula (I) can be purified by the usual physical means, for example by crystallisation or chromatography. S(O) a -A-S(0) D.-Het (I) (VIII) The following Examples illustrate the. preparation of compounds encompassed by the various aspects of the invention and the Reference Examples illustrate the preparation of certain intermediates. EXAMPLE 1 Compounds A, B and C i) Potassium t-butoxide (lO.Og) was added to 2-mercaptopyrimidine (10.Og) in dimethylforma ide (DMF) (lOOml) and the mixture was stirred at ambient temperature for 15 minutes, then l-chloro-3-iodopropane (9.6ml; 18.23g) was added and the mixture stirred for a further 2 hours. A solution prepared by adding potassium t-butoxide (5.0g) to 4,5-diphenylimidazole- 2-thiol (11.25g) in DMF (100ml) was then added and the resulting mixture was stirred overnight. The reaction mixture was concentrated under reduced pressure to leave an orange-red oil. Water (100ml) was added and the product was extracted into ethyl acetate (3x150ml). The organic solution was dried over magnesium sulphate and then concentrated under reduced pressure to leave a red oil. Chromatography on silica, eluting with dichloromethane / ethyl acetate (85:15) yielded 2-[3-(pyrimidin-2-ylthio)propylthio}-4,5-diphenyl¬ imidazole (13.Og) in the form of a white solid, after recrystallisation from aqueous ethanol, mp 110-115 β C ? [Found:- C,65.2;H,4.91;N,14.1;S,16.1%; Calculated for C 22 H 20 N 4 S 2 ! " C,65.32;H,4.98;N,13.83;S,15.83%3. ii) By proceeding in a similar manner, but replacing the 2-mercaptopyrimidine by 4-mercapto- pyridine and using dichloro ethane / ethyl acetate (75:25) as eluent, there was prepared 2-[3-(pyrid-4-yl- thio)propylthio3-4,5-diphenylimidazole, in the form of a pale yellow solid, after trituration with diethyl ether, p 125-127 β C; [Found:- C,68.0;H,5.15;N,10.4; S,16.3%; Calculated for 23 H 21 N 3 S 2 :- C,68.45;H,5.25; N,10.41;S,15.89%3. iii) By proceeding in a similar manner, but replacing the 2-mercaptopyrimidine by l-methyl-2- mercaptoimidazole and using dichloromethane / ethyl acetate (75:25) and then ethyl acetate as eluents, there was prepared 2-[3-(l-methylimidazol-2-ylthio)- propylthio3-4,5-diphenylimidazole, in the form of a white powder, after trituration with diisopropyl ether, mp 142 β C; [Found:- C,65.2;H,5.62;N,13.9;S 16.1%; Calculated for C 22 H 22 N 4 S 2 :- C,64..99;H,5.45;N,13.78; S,15.77%3. EXAMPLE 2 Compound D A solution of 1 equivalent of 2-[3-(l-methyl- imidazol-2-ylthio)propylthio3- ,5-diphenylimidazole in ethanol was added to a solution of hydrogen chloride in ethanol prepared by adding 3 equivalents of acetyl chloride to. ice-cooled ethanol. The solution was concentrated under reduced pressure and the residue was triturated with diethyl ether to yield 2-[3-(l-methyl- imidazol-2-ylthio)propylthio3-4,5-diphenylimidazole dihydrochloride as a white solid; [Found:- C,51.3; H,5.5;N,11.0;C1,14.0;S,12.3%; Calculated for C 22 H 22 N 4 S 2 .2HC1.2H 2 0:- C,51.26;H,5.44;N,10.87;C1,13.76; S,12.43%]. - EXAMPLE 3 Compounds E and F i) Sodium hydride (0.9g; 80% dispersion in mineral oil) was carefully added to a stirred suspension of 4,5-diphenylimidazole-2-thiol (7.5g) in dry tetrahydrofuran (THF) (300ml) to give a yellow solution. 1,2-Dichloroethane (1.5g) was added and the solution was heated at reflux for 26 hours, then poured into water. The solid was collected and washed with water and then stirred with methanol and dichloro¬ methane (1:1). The solid was collected, washed with diethyl ether, then dissolved in DMF, diluted with diethyl ether and left to recrystallise to give l,2-bis(4,5-diphenylimidazol-2-ylthio)ethane (1.18g) as a white powder, mp 310*C; [Found:- C,72.4;H,4.91; N,10.6;S,12.1%.; Calculated for C 32 H 26 N 4 S 2 Ϊ_ C ' 72 - 42 ' * H,4.94;N,10.56;S,12.08%3. ii) By proceeding in a similar manner, but replacing the sodium hydride by potassium t-butoxide, replacing the THF by DMF and replacing the 1,2-di- chloroethane by l-chloro-3-iodopropane, stirring at ambient temperature overnight and purifying the crude product by chromatography on silica, eluting with dichloromethane / ethyl acetate (3:2), there was prepared 1,3-bis(4,5-diphenylimidazol-2-ylthio)- propane, as a white solid, after crystallisation from ethyl acetate, mp 240 β C; [Found:- C,72.9;H,5.2; N,10.1;S,11.3%; Calculated for C 33 H 28 N S 2 : ~ c » 72 * 76 ' * H,5.18;N,10.29;S,11.77%3. EXAMPLE 4 Compound G By proceeding in a similar manner to that described in Example 1 but replacing the 2-mercapto¬ pyrimidine by 4,6-dimethyl-2-mercaptopyrimidine and using dichloromethane / ethyl acetate (4:1) as eluent, there was prepared 2-[3-(4,6-dimethylpyrimidin-2-yl- thio)propylthio3-4,5-diphenylimidazole, in the form of a pale green solid, after trituration with diethyl ether, mp 122-124 β C; [Found:- C,66.5;H,5.54;N,12.9; S,14.8%; Calculated for C 24 H 24 N 4 S 2 : ~ C » 66 -63*H,5.59; N,12.95;S,14,82%3. EXAMPLE 5 Compound H A mixture of 4,5-diphenylimidazole-2-thiol (5;04g) and potassium tert-butoxide (2.35g) in dry dimethylformamide (DMF) (75ml) was stirred for 15 minutes to give a yellow suspension. A solution of l-methyl-2-(3-chloropropylsulphonyl)imidazole (4.68g) in dry DMF (10ml) was added and the resulting mixture was stirred overnight at ambient temperature. The mixture was concentrated under reduced pressure and the residue was dissolved in ethyl acetate and twice washed with water. After drying over magnesium sulphate, the solution was concentrated under reduced pressure. Chromatography of the residue on silica, eluting with ethyl acetate afforded 2-[3-(l-methylimidazol-2-yl- sulphonyl)propylthio3-4,5-diphenylimidazole, in the form of a white solid after crystallisation from ethyl acetate, mp 143-144 β C; [Found:- C,59.8;H,5.04;N,12.7; S,14.6%; Calculated for C 22 H 22 N 4 0 2 S 2 :- C,60.25;H,5.06; N,12.78;S,14.62%3. EXAMPLE 6 Compounds I and J i) By proceeding in a similar manner to that described in Example 1, but replacing the initial use of potassium tert-butoxide by sodium hydride (80% dispersion in mineral oil) and replacing the 2-mercaptopyrimidine by 4-methyl-2-mercapto-l,2,4- triazole, stirring overnight after the addition of l-chloro-3-iodopropane and using ethyl acetate followed by ethyl acetate / methanol (4:1) as eluents, there was prepared 2-[3-(4-methyl-l,2,4-triazol-3-ylthio)ρropyl- thio3-4,5-diphenylimidazole, in the form of a white solid from ethyl acetate, mp 141-142 β C; [Found:- C,61.5;H,5.0;N,17.5;S,15.6%; Calculated for C 21 H 21 N 5 S 2 : " C » 61 ' 89 * H ' 5 ' 19 ' N ' 17 '18;S,15.74%]. ii) By proceeding in a similar manner to that described in Example 1, but omitting the initial use of potassium tert-butoxide and replacing the 2-mercapto¬ pyrimidine by the sodium salt of l-methyl-5-mercapto- tetrazole, stirring overnight after the addition of l-chloro-3-iodopropane and using ethyl acetate / dichloromethane (1:2) as eluent, there was prepared 2-[3-(l-methyltetrazol-5-ylthio)propylthio]-4,5- diphenylimidazole in the form of a white solid from ethyl acetate, mp 131 β C; [Found:- C,58.8;H,4.86; N,21.0;S,15.7%; Calculated for C 2£) H 20 N 6 S 2 :- C,58.79; H,4.93;N,20.57;S,15.70%3. EXAMPLE 7 Compound K Potassium tert-butoxide (0.56g) was added to a solution of 2-mercapto-4,5-dipyrid-2-ylimidazole (1.27g) in dry DMF (30ml). After stirring for 15 minutes, a solution of 2-(3-chloropropylthio)-4,5- diphenylimidazole (1.64g) in dry DMF (10ml) was added. The resulting mixture was stirred overnight at ambient temperature and then concentrated under reduced pressure. The residue was taken up in ethyl acetate (100ml) and twice washed with water, then dried over magnesium sulphate. Chromatography on silica, eluting with ethyl acetate, afforded a yellow solid which was dissolved in ethanol (50ml) and treated with a solution of hydrogen chloride in ethanol. After stirring for 30 minutes, the solution was concentrated under reduced pressure and the residue was triturated with diethyl ether to give l-(4,5-diphenylimidazol-2-yl hio)-3- [(4 ,5-dipyrid-2-yl)imidazol-2-ylthio3propane dihydrochloride, as a yellow solid; [Found:- C,57.7; H,5.1;N,12.7;C1,10.6;S,9.6%; Calculated for C 31 H 26 N 6 S 2 .2HC1.1|H 2 0:- C,57.59;H,4.83;N,13.0;C1,10.97; S,9.92%3. EXAMPLE 8 Compound L By proceeding in a similar manner to that described in Example 5, but replacing the l-methyl-2- (3-chloropropylsulphonyl)imidazole with l-methyl-5- (3-chloropropylsulphonyl)tetrazole, there was prepared 2-[3-(l-methyltetrazol-5-ylsulphonyl)propylthio3-4,5- diphenylimidazole, as a crystalline solid from ethyl acetate, mp 157-158 β C; [Found:- C,54.1;H,4.44;N,19.2; S,14.5%; Calculated for C^H^NgO^:- C,4.53;H,4.58; N,19.08;S,14.56%3. EXAMPLE 9 Compounds M and N i) By proceeding in a similar manner to that described in Example 1, but replacing the 2-mercapto¬ pyrimidine by 2-mercaptoimidazole and using ethyl acetate as eluent, there was prepared 2-[3-(imidazol- 2-ylthio)propylthio3-4,5-diphenylimidazoϊe, in the form of a white solid, after crystallisation from ethyl acetate, mp 163-164°C; [Found:- C,63.9;H,5.0;N,14.4; S,16.2%; Calculated for C 2i H 20 N 4 S 2 : " C » 64 ' 25 ' *H » 5 ** 14 ? N,14.27;S,16.34%. ii) By proceeding in a similar manner to that described in Example 1, but replacing the 2-mercaptc- pyrimidine by l-methyl-2-mercaptoimidazole and replacing the l-chloro-3-iodopropane with l-chloro-4- iodobutane and using ethyl acetate as eluent, there was prepared 2-[4-(l-methylimidazol-2-ylthio)butylthio - 4,5-diphenylimidazole, as a solid after trituration with diethyl ether and recrystallisation from ethyl acetate, mp lll-112 β C; [Found:- C,65.9;H,5.73;N,13.3; S,15.3%; Calculated for C 23 H 24 N 4 S 2 S ~ C » 65 « 68 ' *H ' 5 ' 75 ? N,13.32;S,15.25%], . EXAMPLE 10 Compound O A suspension of 2-[4-(l-methyliraidazol- 2-ylthio)butylthioJ-4,5-diphenylimidazole (2.5g) in dichloromethane (150ml) was treated with m-chloro- perbenzoic acid (7.2g; 72% mixture with water). The mixture was stirred overnight at ambient temperature and then an aqueous solution of sodium metabisulphite was added. The organic phase was washed twice with aqueous sodium bicarbonate and then with water and dried over magnesium sulphate. Concentration under reduced pressure left a foam which was crystallised from ethyl acetate to give 2-[4-(l-methylimidazol- 2-ylsulphonyl)butylsulphonyl]-4,5-diphenylimidazole, mp 149-150 β C; [Found:- C,57.0;H,5.0;N,11.6;S,13.2%; Calculated for C 23 H 24 N 4°4 S 2 S " c ' 57 - 00 ' *H r 5 *°0;N,11.57; S,13.23%3. EXAMPLE 11 Compounds P and Q i) By proceeding in a similar manner to that described in Example 3, but replacing the 1,2-dichloro- ethane by l-chloro-4-bromobutane and purifying the crude product (which was isolated by extraction into ethyl acetate) by chromatography on silica, eluting with dichloromethane / methanol (19:1), there was prepared 1,4-bis<4,5-diphenylimidazol-2-ylthio)butane, as a colourless solid, mp 230-232 β C; [Found:- C,72.8; H,5.4;N,10.01;S,11.6%; Calculated for C 34 H 3£) N 4 S 2 :- C,73.08;H,5.41;N,10.03;S,11.48%3. ii) By proceeding in a similar manner, but replacing the 1,2-dichloroethane by 1, -dibromo- but-2-ene and purifying the crude product (which was isolated by extraction into ethyl acetate) by crystallisation from dichloromethane followed by recrystallisation from isopropanol, there was prepared E-l,4-bis(4,5-diphenylimidazol-2-ylthio)but-2-ene, in the form of a colourless solid, mp 233-235 β C; [Fόund:- C,73.4;H,5.16;N,10.1;S,11.6%; Calculated for C 34 H 28 N 4 S 2 : " C , 7 3.35;H,5.07;N,10.06;S,11.52%3. EXAMPLE 12 Compound R By proceeding in a similar manner to that described in Example 1, but replacing the original use of potassium tert.-butoxide by sodium hydride (80% dispersion in mineral oil), replacing the 2-mercapto- pyriraidine by l-methyl-2-mercaptoimidazole, replacing the l-chloro-3-iodopropane by l-bromo-6-chlorohexane and using ethyl acetate / dichloromethane (7:3) as eluent, there was prepared 2-[6-(l-methylimidazol-2-yl- thioJhexylthio]-4,5-diphenylimidazole, in the form of a white solid, after recrystallisation from ethyl acetate, .p. 107-108 β C; [Found:- C,66.7;H,6.3;N,12.6; S,13.9%; Calculated for C 25 H 2g N 4 S 2 :- C,66.93;H,6.29; N,12.49;S,14.29%3. EXAMPLE 13 Compound S By proceeding in a similar manner to that described in Example 3 ii), but replacing the l-chloro-3-iodopropane by 5 equivalents of 1,9-dibromononane and purifying the crude product by chromatography ori silica, eluting with diethyl ether / cyclohexane (15:85) followed by diethyl ether, there were prepared:- i) from the ether / cyclohexane eluate, 2-(9- bromononylthio)-4,5-diphenylimidazole, as a white solid, after recrystallisation from cyclohexane, m.p. 96-97°C; [Found:- C,62.6;H,6.3;N,6.0;Br,17.4;S,7.0%; Calculated for C 24 H 2 gBrN 2 S - C,63.01;H,6.39;N,6.12; Br,17.47;S,7.01%3; and ii) from the ether eluate, l,9-bis(4,5-diphenyl- imidazol-2-ylthio)nonane, as a white solid, from ethyl acetate, m.p.l99-200 β C; [Found:- C,73.5;H,6.4;N,8.7; S,10.1%; Calculated for C 39 H 40 4 S 2 .0.3C 2 H 5 O 2 CCH 3 :- C,73.68;H,6.52;N,8.55;S,9.79%]. EXAMPLE 14 Compound T By proceeding in a similar manner to that described in Example 7, but replacing the 2-mercapto- 4,5-dipyrid-2-ylimidazole by l-methyl-2-mercapto- imidazole, replacing the 2-(3-chloropropylthio)- ,5-diphenylimidazole by 2-(9-bromononylthio)-4,5- diphenylimidazole (prepared as in Example 13) and eluting with dichloromethane / methanol (3:1), there was prepared 2-[9-(l-methylimidazol-2-ylthio)nonyl- thio]-4,5-diphenylimidazole, as a white solid, after trituration with petrol (b.p. 40-60 β C), m.p. 101-102 β C; [Found:- C,68.4;H,6.95;N,11.5;S,13.0%; Calculated for C 28 H 34 N 4 S 2 : " C,68.53;H,6.98;N,11.42;S,13.07%3. EXAMPLE 15 Compounds AA, AB and AC A stirred suspension of 4,5-diphenylimidazole-2- thiol (5.04g) in dry tetrahydrofuran (150ml) was treated with sodium hydride (60% dispersion in oil;0.88g;22mmol) at the ambient temperature under an inert atmosphere, and stirred for 30 minutes. The resulting solution was treated with l,2-bis(bromo- methyl)benzene (2.64g) and stirred for a further period of 1 hour. The mixture was then heated at reflux for 30 minutes and then. it was poured into brine (200ml). The organic layer was dried over magnesium sulphate and evaporated and the resulting residue was extracted with boiling 2-ethoxyethanol (1x500ml). Concentration of the extract (to about 50ml) gave a solid which was filtered off, washed with diethyl ether and dried, to give 1,2-bis(4,5-diphenyliraidazol-2-ylthiomethyl)- benzene (1.75g), in the form of a colourless solid, m.p. 255-257 β C. [Elemental analysis:- C,74.90; H,5.01;N,9.20;S,10.80%; calculated:- C,75.21;H,4.98; N,9.23;S,10.57%3. By proceeding in a similar manner, but replacing the 1,2-bis(bromomethyl)benzene by the appropriate quantities of 1,3-bis(bromomethyl)benzene and 1,4-bis(bromomethyl)benzene, respectively, there were prepared:- 1,3-bis( ,5-diphenylimidazol-2-ylthiomethyl)benzene in the form of a colourless solid, m.p. 231-232°C [Elemental analysis:- C,75.60;H,5.17;N,8.90;S,10.70%; calculated:- C,75.21;H,4.98;N,9.23;S,10.57%]; and 1,4-bis(4,5-diphenylimidazol-2-ylthiomethyl)benzene in the form of a colourless solid, m.p. 259-260*C [Elemental analysis:- C,74.80;H,4.98;N,9.10;S,10.40%; calculated:- C,75.21;H,4.98;N,9.23;S,10.57%]. EXAMPLE 16 Compounds AD and AE A stirred suspension of 4,5-diphenylimidazole- 2-thiol (10.Og) and l-methyl-2-mercaptoimidazole (4.54g) in dry tetrahydrofuran (300ml) was treated with sodium hydride (60% dispersion in oil;2.66g) under an inert atmosphere at ambient temperature, and stirred for 20 minutes. The resulting solution was treated with l,3-dichloropropan-2-ol (3.8ml) and the mixture was stirred at the ambient temperature for 20 hours. The mixture was then evaporated and the residue was partitioned between water (500ml) and ethyl acetate (500ml). The ethyl acetate solution was dried over magnesium sulphate, and evaporated and the resulting solid residue was subjected to flash chromatography on silica gel, using ethyl acetate as eluent. The first major component obtained was 1,3-bis(4,5-diphenylimidazol-2-ylthio)ρropan-2-ol (1.8g) in the form of a colourless solid, m.p. 225-227 β C [Elemental analysis:- C,70.30;H,5.10;N,9.70; S,11.40%; calculated:- C,70.68;H,5.03;N,9.99;S 11.43%]; and the second major component obtained was 4,5-diphenyl-2-[3-(l-methylimidazol-2-ylthio)-2- hydroxypropylthio3imidazole (3.5g) in the form of a colourless solid, m.p. 198-200 C C [Elemental analysis:- C,62.40;H,5.23;N,13.20;S,15.30%; calculated:- C,62.53; H,5.24;N,13.26;S,15.17%]. EXAMPLE 17 Compound BA A solution of maleic acid (30.47g) in acetone (200ml) was added to a stirred suspension of 4,5-diphenyl-2-[3-(l-methylimidazol-2-ylthio)propyl¬ thio3imidazole (50.82g) in acetone (400ml). The suspension was stirred at ambient temperature; a clear solution formed, then, a solid crystallised. The solid was collected, was washed with diethyl ether and was then dried to give 4,5-diphenyl-2-[3-(l-methylimidazol- 2-ylthio)propylthio]imidazole dimaleate in the form of a white powder; m.p. 92-94 β C. [Elemental analysis:- C,55.0;H,4.7;N,8.6;S,9.7%; calculated for C 30 H 30 N 4°8 S 2 :H 2 O: ' C » 54«*87 ' ,H ' 4«91 ' ,N » 8 ' 53 ' ,S , 9 ** 76 % . EXAMPLE 18 Compounds BB to CC By carrying out processes similar to those described herein, more especially in the Examples and Reference Examples, there were prepared the following compounds:- 4,5-Diphenyl-2-[3-(3-amino-l,2,4-triazol-5-ylthio)- propylthio3imidazole, m.p. 171-173 β C from ethanol; 4,5-Diphenyl-2-[3-(pyrid-2-ylthio)propylthio]imidazole, m.p. 120-122 β C after chromatography on silica eluting with a mixture of dichloromethane and ethyl acetate; E-4,5-Diphenyl-2-[4-(1-methylimidazol-2-ylthio)but-2- enylthio3imidazole,- m.p. 125-127 β C from t-butyl methyl ether; ,5-Diphenyl-2-[3-(ρyrimidin-2-ylsulphonyl)propylthio]- imidazole, m.p. 144-145°C from ethyl acetate; ,5-Diphenyl-2-[4-(ρyrimidin-2-ylsulphonyl)butylthio - imidazole, m.p. 138-139 β C from ethyl acetate; ,5-Diphenyl-2-[3-(ρyrid-2-ylsulphinyl)propylthio3- imidazole, m.p. 108-109 β C from ethyl acetate; 4,5-Diphenyl-2-[4-(pyrimidin-2-ylthio)butylthio3imid¬ azole, m.p. 110 C C from diethyl ether; 1,6-Bis(4,5-diphenylimidazol-2-ylthio)hexane, m.p. 205-207°C from acetonitrile; 4,5-Bis(4-methylphenyl)-2-[3-(l-methylimidazol-2-yl- thio)propylthio]imidazole, m.p. 141-142 β C from a mixture of ethyl acetate and cyclohexane; 4,5-Bis(4-methoxyphenyl)-2-[3-(pyrimidin-2-ylsulph- onyl)propylthio3imidazole, m.p. 57-63 β C after trituration with light petroleum (b.p. 60 - 80 β C. ); 4,5-Diphenyl-2-[4-(imidazol-2-ylthio)butylthio3imid¬ azole, m.p. 155-156 β C from, ethyl acetate; 4,5-Diphenyl-2-[3-(pyrid-4-ylsulphonyl)propylthio3imid¬ azole, m.p. 171-173 β C from ethyl acetate; 4,5-Diphenyl-2-[3-(pyrid-2-ylsulphonyl)propylthio3imid¬ azole, m.p. 143-144 β C after trituration with diethyl ether; 4,5-Diphenyl-2-[4-(pyrid-2-ylthio)butylthio]imidazole, m.p. 122-124 β C from a mixture of toluene and light petroleum; l,5-Bis(4,5-diρhenylimidazol-2-ylthio)pentane, m.p. 211-213 β C from ethyl acetate; l,4-Bis(4,5-diphenylimidazol-2-ylthio)but-2-yne, m.p. 200-202 β C from ethyl acetate; ,5-Diphenyl-2-[4-(l-methylimidazol-2-ylthio)but-2- ynylthio]imidazole, m.p. 150-152 β C from isopropanol; 4,5-Bis(4-fluorophenyl)-2-[3-(l-methylimidazol-2-yl- thio)propylthio3imidazole, m.p. 178-180 β C from a mixture of ethyl acetate and cyclohexane; 4,5-Bis(4-methoxyphenyl)-2-[4-(pyrimidin-2-ylsulph- onyDbutylthio3imidazole, m.p. 82-84 β C after trituration with light petroleum; 4,5-Diphenyl-2-[4-(pyrid-2-ylsulphonyl)butylthio3imid¬ azole, m.p. 107-108 β C from ethyl acetate; 4,5-Diphenyl-2-[4-(pyrid-2-ylsulphinyl)butylthio]imid¬ azole, m.p. 82-84 β C after trituration with diisopropyl ether; 4,5-Diphenyl-2-{3-[4(5)-methylimidazol-2-ylthioIpropyl- thio}imidazole, m.p. 185 β C from a mixture of ethyl acetate and light petroleum; 4,5-Diphenyl-2-[5-(imidazol-2-ylthio)pentylthio3imid¬ azole, m.p. 165-166°C from a mixture of ethanol and ethyl acetate; ,5-Diphenyl-2-[3-(imidazol-2-ylthio)propylthio]imid¬ azole dihydrochloride, m.p. 208-210°C after trituration. with diethyl ether [Elemental analysis:- C,53.8;H,4.7; N,11.9;C1,15.68;S,13.6%; calculated for C 21 H 20 N 4 S 2 :2HC1:- C,54.17;H,4.76;N,12.0;C1,15.23; S,13.77%]; 4,5-Diphenyl-2-[3-(imidazol-2-ylthio)propylthio]imid¬ azole dimaleate, m.p. 162-164°C from water [Elemental analysis:- C,54.6;H,4.5;N,8.9;S,10.2%; calculated for C 29 H 28 N 4°8 S 2 ϊ0,5H 2 Oϊ " C,54.97;H,4.61;N,8.84;S,10.12%]; Z-1,4-Bis(4,5-diphenylimidazol-2-ylthio)but-2-ene, m.p. 215-217*C from isopropanol, [Elemental analysis:- C,72.1;H,5.14;N,9.7;S,11.3;water,0.9%; calculated for C 34 H 2g N 4 S 2 :0.5H 2 O:- C,72.18;H,5.17;N,9.90;S,11.33; water,1.59%]; 4,5-Diphenyl-2-[4-(pyrid-2-ylsulphonyl)butylthio]imid- azole hydrochloride, m.p. 156-158°C after trituration with diethyl ether [Elemental analysis:- C,58.8; H,5.03;N,8.2;Cl,7.2;S,13.0;water,1.7%; calculated for C 24 H 23 N 3 S 2°2 :HClϊ0,4H 2 Oϊ " c » 58 ' 49 - ϊH , s *> 2 3? N » 8» 52; Cl,7.42;S,13.01;water,1.46%3; and 4,5-Diphenyl-2-[4-(imidazol-2-ylsulphonyl)butylthio3im¬ idazole, m.p. 215°C from ethanol [Elemental analysis:- C,59.1;H,5.0;N,12.6;S,14.5%; calculated for C 22 H 22 N 4 S 2°2 ϊH 2 0: " C,59.3;H,4.94;N,12.58;S,14.4%]. REFERENCE EXAMPLE 1 Sodium hydride (1.6g; 80% dispersion in mineral oil) was carefully added to a stirre solution of l-methylimidazole-2-thiol (5.7g) in dry tetrahydrofuran (lOOral). After 15 minutes, l-chloro-3-iodopropane (10.2g) was added and the mixture was stirred overnight at ambient temperature. The mixture was concentrated under reduced pressure and the residue was partitioned between water(50ml) and ethyl acetate (75ral). The organic solution was washed with water, dried over magnesium sulphate and concentrated under reduced pressure to yield l-methyl-2-(3-chloropropylthio)- imidazole as a yellow oil which was utilised without further purification. A solution of l-methyl-2-(3-chloropropylthio)- imidazole (8.8g) in dry dichloromethane (100ml) was cooled to 10°C and -chloroperbenzoic acid (27.6g; 72% mixture with water) was added. The mixture was stirred for 12 hours at ambient temperature and then filtered. The filtrate was washed twice with 10% aqueous sodium metabisulphite, then with 10% aqueous sodium bicarbonate and finally twice with water, then dried over magnesium sulphate. Concentration under reduced pressure left a yellow oil that crystallised on standing. Chromatography of the solid on silica eluting with diethyl ether provided l-methyl-2-(3- chloropropylsulphonyl)imidazole as a yellow oil. REFERENCE EXAMPLE 2 Potassium t-butoxide (12.3g) was added to 4,5-diphenyl-2-mercaptoimidazole (25.2g) in dry DMF (300ml) and the mixture was stirred at ambient temperature for 30 minutes, then l-chloro-3-iodopropane (21.Og) was added and the mixture was stirred overnight. The residue left after concentrating under reduced pressure was partitioned between ethyl acetate and water. The aqueous fraction was twice extracted with ethyl acetate and then the combined ethyl acetate solutions were washed with water and dried over magnesium sulphate. Chromatography on silica, eluting with chloroform provided 2-(3-chloropropylthio)-4,5- diphenylimidazole, in the form of a white solid from ethyl acetate / petrol, m.p. 147-150 β C; [Found:- C,65.6;H,5.21;N,8.4;C1,10.9;S,9.8%; Calculated for C 18 H 17 C1 2 S:- C,65.74;H,5.21;N,8.52;C1,10.78;S,9.75%]. In clinical practice 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 dose employed will be determined by the physician, and depends upon the desired therapeutic effect, the route of administration and the duration of the treatment, and the condition of the patient. In the adult, the doses are generally from 0.5 to 70, preferably 1 to 10, g/kg body weight per day by oral administration. The following Examples illustrate pharmaceutical compositions according to the present invention. COMPOSITION EXAMPLE 1 No. 2 size gelatin capsules each containing:- 2-[3-(l-methylimidazol-2-ylthio) ropyl¬ thio]-4,5-diphenylimidazole 20 mg lactose 100 mg starch 60 mg dextrin 40 mg magnesium stearate 1 mg were prepared in accordance with the usual procedure. COMPOSITION EXAMPLE 2 No. 2 size gelatin capsules each containing:- 1,2-bis(4,5-diρhenylimidazol-2-ylthiomethyl)- benzene 20 mg lactose 100 mg starch 60 mg dextrin 40 mg magnesium stearate 1 mg were prepared in accordance with the usual procedure. COMPOSITION EXAMPLE 3 Ko. 2 size gelatin capsules each containing:- 2-[3-(imidazol-2-ylthio)propylthio]- 4,5-diphenylimidazole 20 mg lactose 100 mg starch 60 mg dextrin 40 mg magnesium stearate 1 mg were prepared in accordance with the usual procedure.

Claims: CLAIMS 1. An imidazole derivative of the general formula: wherein: A represents a methylene group or a group -C^- '-CH^-- wherein A 1 represents a direct bond, a linear alkanediyl, alkenediyl or alkynediyl group containing up to 14 carbon atoms, or a hydroxymethylene group, or A' represents a phenylene group optionally substituted by 1 to 4 substituents selected from halogen atoms, alkyl groups (optionally substituted by one or more halogen atoms) , alkoxy, alkylthio, alkylamino, carboxy and alkoxycarbonyl groups; R 1 and R 2 are the same or different and each represents a hydrogen or halogen atom, an alkyl group (optionally substituted by one or more halogen atoms) , or an alkoxy, alkylthio, alkylamino, carboxy or alkoxycarbonyl group; a and b are the same or different and each represents 0, 1 or 2; and Het represents a heterocyclic group containing from 5 to 7 ring atoms chosen from carbon, nitrogen, sulphur and oxygen atoms, optionally substituted by one or two substituents independently selected from:- halogen atoms, alkyl groups (optionally substituted by one or more halogen atoms) , hydroxy, amino, alkoxy, alkylthio, alkylamino, carboxy, alkoxycarbonyl and pyridyl groups, and phenyl groups [optionally, substituted by one or more substituents selected from halogen atoms, alkyl groups (optionally substituted by one or more halogen atoms) , and alkoxy, alkylthio, alkylamino, carboxy and alkoxycarbonyl groups] ; and pharmaceutically acceptable salts thereof; wherein all alkyl groups and moieties, unless otherwise indicated, are straight- or branched-chain and contain from 1 to 5 carbon atoms; and halogen atoms, unless otherwise indicated, are fluorine, chlorine, bromine or iodine atoms; for use in the preparation of a pharmaceutical composition for the treatment, of a condition, which can be ameliorated by administration of an inhibitor of acyl coenzyme-A: cholesterol-O-acyl transferase. 2. A compound according to claim 1 for use in the preparation of a pharmaceutical composition for the treatment of atherosclerosis, hyperlipidaemia, cholesterol ester storage disease or atheroma in vein grafts. 3. An imidazole derivative of general formula I, as defined in claim 1, or a pharmaceutically acceptable salt thereof, provided that when R 1 and R 2 are identical and each represents a fluorine, chlorine or bromine atom or a trifluoromethyl, methoxy or methylthio group in the para position and A represents a methylene, 1,2-ethanediyl, 1,3-propanediyl, 2-hydroxy-l,3-propanediyl or 1,4-butanediyl group then Het represents other than a group of general formula: wherein R 3 represents a hydrogen atom or a methyl group and the symbols R 4 are identical and each represents a fluorine, chlorine or bromine atom or a trifluoromethyl, methoxy or methylthio group in the para position, for use in a method of treatment of the human or animal body by therapy. 4. A compound according to claim 3 for use in a method of treatment of the human or animal body by therapy of atherosclerosis, hyperlipidaemia, cholesterol ester storage disease or atheroma in vein grafts. 5. An imidazole derivative of general formula I, as defined in claim 1 or a pharmaceutically acceptable salt thereof, provided that:- (1) when R-*- and R 2 are identical and each represents a fluorine, chlorine or bromine atom or a trifluoro¬ methyl, methoxy or methylthio group in the para position and A represents a methylene, 1,2-ethanediyl, 1,3-propanediyl, 2-hydroxy-l,3-propanediyl, or 1,4-butanediyl group, then Het represents other than a group of formula (VIII) , wherein R 3 represents a hydrogen atom or a methyl group and the symbols R 4 are identical and each represents a fluorine, chlorine or bromine atom or a trifluoromethyl, methoxy or methylthio group in the para position; and (2) when A represents a 1,3-propanediyl or 2-hydroxy- 1,3-propanediyl group, R 1 and R 2 both represent hydrogen atoms, and a and b both represent zero, then Het represents other than a group of formula (VIII) wherein R 3 represents a hydrogen atom and the symbols R 4 both represent hydrogen atoms. 6. A compound according to claim 5 wherein at least one of the symbols has a value selected from the following:- (i) A represents a group -CH2-A--CH 2 - wherein A 1 represents a direct bond, a linear alkanediyl, alkenediyl or alkynediyl group containing up to 7 carbon atoms or a hydroxymethylene group, or a substituted or unsubstituted phenylene group; (ii) R 1 and R 2 are the same or different and each represents a hydrogen or halogen atom, or an alkyl or alkoxy group; and (iii) Het represents an optionally substituted 5- or 6-membered heterocyclic group containing up to 4 nitrogen atoms, unsubstituted.or substituted by alkyl, amino, pyridyl or optionally substituted phenyl. 7. A compound according to claim 5 or 6 wherein (i) A 1 represents a methylene group or a linear alkanediyl group containing 2, 3, 4 or 7 carbon atoms or a vinylene or ethynylene group or an unsubstituted phenylene group; (ii) R 1 and R 2 are the same or different and each represents a hydrogen atom or a fluorine atom or a methyl or methoxy group in the 4-position; and/or (iii) Het represents pyrimidin-2-yl, pyrid-2-yl, pyrid-4-yl, imidazol-2-yl, l,2,4-triazol-3-yl, or tetrazol-5-yl, group unsubstituted or substituted by methyl, amino, pyrid-2-yl or optionally substituted phenyl. 8. A compound according to claim 1 hereinbefore identified as any one of compounds A to E, G to AC and AE to CC. 9. A process for the preparation of a compound of general formula (I) as defined in claim 5 which comprises: (A) when A, R 1 , R 2 , b and Het are as defined in claim 5 and a represents zero, the reaction of a salt of general formula: wherein R 1 and R 2 are as defined in claim 5 and M represents an alkali metal atom, with a compound of formula: Z^-A-SfOJ- b -Het (III) wherein A, b and Het are as defined in claim 5 and Z 1 represents a chlorine, bromine or iodine atom, or an alkyl- or aryl-sulphonyloxy group; (B) when A, R 1 , R 2 ., a and Het are as defined in claim 5 and b represents zero, the reaction of a salt of formula: Het-S~ M+ (V) wherein Het and M are as hereinbefore defined, with a compound of general formula: wherein A, R 1 , R 2 and a are as defined in claim 5 and Z 2 represents a chlorine, bromine or iodine atom, or an alkyl- or aryl-sulphonyloxy group; (C) when the compound of formula (I) conforms to the general formula: wherein A, R 1 and R 2 are as defined in claim 5, the reaction of a salt of formula (II) with a compound of formula: Z^-A-Z 2 (VII) wherein A, Z 1 and Z 2 are as hereinbefore defined; (D) when A, R 1 , R 2 and Het are as defined in . claim 5 and a and b are both zero, the reaction of a salt of formula (II) and a salt of formula (V) with a compound of formula (VII) wherein the various symbols are as hereinbefore defined; (E) when A, R 1 , R 2 and Het are as hereinbefore defined and at least one of a and b represents 1 or 2, the oxidation of a compound of formula (I) , wherein A, R 1 -and Het are as hereinbefore defined and a and/or b is less than in the desired product; optionally followed by the conversion of a compound of general formula (I) into another compound of general formula (I) ; optionally followed by conversion of a compound of general formula (I) into a pharmaceutically acceptable salt thereof. 10. A pharmaceutical composition which comprises an imidazole derivative of formula (I) as defined in claim 3, or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable carrier or coating. 11. A pharmaceutical composition useful in the treatment of a condition which can be ameliorated by. administration of an inhibitor of acyl coenzyme-A: cholesterol-O-acyl transferase 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 salt thereof. 12. A method or the treatment of a human or animal host suffering from, or subject to, a condition which can be ameliorated by administration of an inhibitor of acyl coenzyme-A: cholesterol-O-acyl transferase which comprises the administration to said host of an amount effective to ameliorate said condition of an imidazole derivative of general formula (I) as defined in claim 1, or a pharmaceutically acceptable salt thereof. 13. An agent for use in the treatment of a condition which can be ameliorated by administration of an inhibitor of acyl coenzyme-A: cholesterol-O-acyl transferase which comprises an imidazole derivative of the general formula: wherein: A represents a methylene group or a group -CH 2 -A*-CH2- wherein A 1 represents a direct bond, a linear alkanediyl, alkenediyl or alkynediyl group containing up to 14 carbon atoms, or a hydroxymethylene group, or A' represents a phenylene group optionally substituted by 1 to 4 substituents selected from halogen atoms, alkyl groups (optionally substituted by one or more halogen atoms) , alkoxy, alkylthio, alkylamino, carboxy and alkoxycarbonyl groups; R 1 and R 2 are the same or different and each represents a hydrogen or halogen atom, an alkyl group (optionally substituted by one or more halogen atoms) , or an alkoxy, alkylthio, alkylamino, carboxy or alkoxycarbonyl group; a and b are the same or different and each represents 0, 1 or 2; and Het represents a heterocyclic group containing from 5 to 7 ring atoms chosen from carbon, nitrogen, sulphur and oxygen atoms, optionally substituted by one or two substituents independently selected from:- halogen atoms, alkyl groups (optionally substituted by one or more halogen atoms) , hydroxy, amino, alkoxy, alkylthio, alkylamino, carboxy, alkoxycarbonyl and pyridyl groups, and phenyl groups [optionally substituted by one or more substituents selected from halogen atoms, alkyl groups (optionally substituted by one or more halogen atoms) , and alkoxy, alkylthio, alkylamino, carboxy and alkoxycarbonyl groups] ; and pharmaceutically acceptable salts thereof; wherein all alkyl groups and moieties, unless otherwise indicated, are straight- or branched-chain and contain from 1 to 5 carbon atoms; and halogen atoms, unless otherwise indicated, are fluorine, chlorine, bromine or iodine atoms.

Inventors: BRIDGE ANDREW WILLIAM, HARRIS NEIL VICTOR, LYTHGOE DAVID JOHN, SMITH CHRISTOPHER, BRIDGE, ANDREW, WILLIAM, HARRIS, NEIL, VICTOR, LYTHGOE, DAVID, JOHN, SMITH, CHRISTOPHER
Applicants: RHONE POULENC SANTE, RHONE-POULENC SANTE
Application year: 1990
Main classification: C07D403
IPC codes: A61K31, A61P3, A61P9, A61P43, C07D233, C07D401, C07D403