GB2280675A

GB2280675A - ACAT-inhibiting imidazoles

Info

Publication number: GB2280675A
Application number: GB9415873A
Authority: GB
Inventors: Massimiliano Palladino; Ermes Vanotti; Manuela Villa; Massimo Bani; Rita Bormetti; Vincenzo Olgiati
Original assignee: Farmitalia Carlo Erba SRL; Carlo Erba SpA
Current assignee: Pfizer Italia SRL
Priority date: 1993-08-06
Filing date: 1994-08-05
Publication date: 1995-02-08
Also published as: GB9415873D0; ITMI931806A0; JPH07149733A; ITMI931806A1; DE4428025A1; IT1270976B

Description

1 11 :iA 2280675 COMPOUNDS THAT ARE INHIBITORS OF ACYL

ENZYME-A-CHOLESTEROL-O-ACYL- TRANSFERASE AND HAVE THERAPEUTIC ACTIVITY, THEIR USE AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM The present invention regards heteroaromatic thioethers having inhibiting activity on the enzyme acyl enzyme-A-cholesterol-o-acyl-transferase (ACAT), their preparation and their therapeutic use as well as the pharmaceutical compositions containing them. In the European patent application no. 520552 of the same Applicant are described and claimed compounds represented by the following general formula L (HET)Ar-X-CH2_Y-CH2-O-R (1) where:

(HET)Ar represents an aryl or heteroaryl nucleus mono-,bi- and tricyclic possibly substituted, X represents -0- or -S-; Y represents -CO-, a linear or branched alkyl having from 0 to S carbon atoms, -CHOR,, in which R, is hydrogen or an acyl group derived from an aliphatic, aromatic or heterocyclic carboxylic acid, with the condition that R, is not hydrogen when (HET)Ar represents a guanine or adenosine group, -C=N-R2, in which R 2 is hydrogen or a linear or branched alkyl having from I to 10 carbon atoms, OH, an alkoxyl having from I to 10 carbon atoms, anaryloxyl, an arylalkoxyl, -NH 21 -NHCONH2, -NHCSNH2; and R represents a phenyl substituted in position para with a carboxylic or (Cl-C20) alkoxycarbonyl group, in which the alkoxyl group can be linear or branched.

A hypolipidaernic action is described for these compounds which is able to increase the serum levels of HDL and lower those of triglycerides and of LDL cholesterol.

It has now been discovered that a family of aromatic thioethers, as subsequently identified and specified, has ACAT inhibiting activity whereby they present a hypolipidaemic activity accompanied by an antiatherosclerosis action, thus interfering with the accumulation of cholesterol esters and with the development of the atheromasic plaque.

The ACAT enzyme, catalyzing the transfer of a fatty acid from Coenzyme A to cholesterol, is able to regulate the intracellular esterification of cholesterol.

This action is exhibited in the various tissues where this enzyme is present: intestine, liver, arterial walls and macrophages.

In the intestine ACAT plays a fundamental role in the absorption of cholesterol, in that in order for the exogenous cholesterol to be absorbed and secreted in the chylomicrons, it must be esterified in the intestinal walls. In the liver the 2 11 esterification by ACAT of the cholesterol therein is necessary for the secretion process of the VLDL.

Consequently, therapeutic agents able to effectively inhibit the action of ACAT exert a hypolipidaemic action, preventing the absorption of cholesterol in the intestine as well as its systemic secretion by the liver.

It has been demonstrated that, during the atherosclerotic process, the activity of this enzyme is markedly increased and an accumulation of cholesterol esters is present in the arterial walls and in the macrophages therein residing.

The importance that compounds with ACAT inhibiting activity can have is therefore obvious.

The compounds being object of the invention are representable, in general terms, by structure 11.

Het-S-CH 2 -Y-CH2-0-R (11) where: Het = 4,5-diphenylimidazole-2-il; Y = -CO-; -(CH2)n- where O<n<10; -CHOH-, meaning the racemic mixture as well as each of the two chiral forms; -C=N-R2 where R2=0H, alkoxy Cl-Clo, omega-hydroxy alkoxy Cl-Clo, -NHCONH 2; R = phenyl substituted in para with a carboxyl or an alkoxy-carbonyl C I- C20 group where the alkoxy can be linear or branched.

The compounds of formula II are novel, as they have never been described in literature, with the exception of those for which Y= -CHOH, exemplified in the above European patent application no. 520552, for which instead the present invention envisages the use as ACAT inhibitors.

It is worthwhile noting that the new compounds of formula II are characterized, as seen in the results of the preliminary pharmacological experiments, by an exceptional hypolipidaemic activity which is not envisaged by the properties of similar compounds described in the above EP-A-520552.

Therefore, a first subject of the present invention consists in the compounds having v 3 I 1 the previous formula II as long as Y differs from -CHOH.

A second subject of the present invention is constituted by the pharmaceutical compositions containing as active ingredient a compound of formula II in which Y is different from -CHOH.

Another subject of the present invention lies in the use of the compounds of formula II as ACAT inhibitors and as antiathero-scierotic drugs without any limitation regarding the purport indicated by the diverse substituents.

The examples which follow illustrate in a non limitative manner the preparation of the compounds in this invention.

The general method for the preparation of the compounds of the present invention envisages the reaction of 4,5-diphenylimidazole-2-thiol with an epoxide having the formula:

C2-CH-CH2-0-R N 0/ or with a haloketone with the formula: X-CH2-CO-CH2-0-R or with a halide with the formula: X-CH2-(C112)n-CE12-0-R where: R is as defined previously, X = Cl, Br, I; 0<n<1O.

In particular, the epoxide, racemic or optically active, is used for the synthesis of the products in examples 1-4.

The haloketone is used for the synthesis as examples 11-20.

The products in examples 6-10 are obtained reacting the compound of example 5 with the opportune hydroxylamine or with semicarbazide.

The reactions are carried out in the presence of a protic or aprotic polar organic solvent, such as alcohol, dimethylformarnide, dimethyisulfoxide and the like, preferably in the presence of a basic catalyst chosen substantially from the class of the sterically hindered tertiary amines, such as trialkylamine, 2,6-lutidine, pyridine etc.

The reaction is preferentially performed at room temperature even though sometimes it may be convenient, in order to accelerate the course there of, to gently heat to in example 5, and the halide for 4 :_1 temperatures between room and IOOOC and preferably to the reflux temperature of a lower alcohol, such as ethanol or isopropanol.

The reaction is generally complete after a period of time which can vary from I to 24 hours depending on the substrate and the catalyzer being used.

At the end of the reaction, the crystallized product is filtered or the solvent is removed and the residue is purified by classical crystallization methods from suitable solvents or by their mixtures by chromatography.

The following examples provide details on the compounds of the invention. EXAMPLE 1 2-j 3-[(p-isobutyloxycarbonyl)-phenoxy3-2-hydroxy-propylthio -4,5- diphenylimidazole.

A solution of isobutyl p-(2,3-epoxy)-propyloxybenzoate (9.9g; 39.6 mM) in absolute ethanol (50 ml) is added dropwise to a suspension of 4,5diphenylimidazole-2-thiot (10 g; 39.6 mM) in absolute ethanol (100 ml) and 2,6-lutidine (I ml) at 900C, under stirring in nitrogen atmosphere. The reaction terminates after 2 h.

The limpid solution is cooled, concentrated and taken with ethyl acetate, the organic phase is subsequently washed with aqueous solutions saturated with sodium bicarbonate and sodium chloride, dehydrated with anhydrous sodium sulfate and concentrated under vacuum to a dry substance. The crude material (20 g) is crystallized from boiling n-heptane by adding a little ethanol.

17.2 g (34.3 mM) of crystalline product are obtained. Yield 86%, m.p. 1351380C. The following derivatives are prepared using the same method:

EXAMPLE 2 2-E(O-isobutyloxycarbonyl)-phenoxy]-2(R)-hydroxy-propylthi4,5diphenylimid azole.

From isobutyl p-E2(S),3,epoxy3-propyloxybenzoate, yield 50%, m.p. 1001010C, alpha D(O.5% in acetone) = -26.89 EXAMPLE 3

2--Ep-isobutyloxycarbonyl)-phenocy]-2(S)-hydroxy-propylthi4,5diphenylimid azole From isobutyl p-12(R),3-epoxyj-propyloxybenzoate, yield 56%, m.p. 68-690C, alphaD(O.5% in acetone) = +26.89 EXAMPLE 4 2-(P-carboxy)-phenoxy3-2- hydroxypropylthioI -4,5-diphenyl imidazole. From p-(2,3-epoxy)- propyloxybenzoic acid, yield 58%, m.p. 219-2210C 1 is EXAMPLE 5 2- 1 3-[(p-isobutyloxycarbonyt)-phenoxy3-2-oxo-propylthio -4,5diphenylidazole To a solution of 4,5-diphenylimidazole-2-thiol (5 g; 19.8 mM) in absolute ethanol (50 ml) and 2,6-lutidine (2.8 ml; 23.8 mM) is added dropwise a solution of isobutyl p-(3-bromo-2-oxo)-propyloxy-benzoate (6.5 g; 19.8 mM) in absolute ethanol (100 ml). The reaction mixture is stirred at room temperature for I hour. The solvent is evaporated, the residue taken with ethyl acetate, washed with an aqueous solution saturated with sodium bicarbonate and dehydrated on anhydrous sodium sulfate.

The solid obtained after evaporation of the solvent is crystallized from petroleum ether, filtered and dried. 8.8 g (17.56 mM) of product are obtained.Yield 88%, m.p. 149-1500C.

EXAMPLE 6

2-f -E(p-isobutyloxycarbonyl)-phenoxY]-2-hydroxymino-propylthi4,5diphenylimida zol.

A mixture composed of 2-E(P-isobutyloxycarbonyl)-phenoxY)-2-oxo-propylthi+4,5-diphenylimidazole (8 g; 16 mM), imidazole (6.5 g; 96 mM) and hydroxylamine hydrochloride (5. 6 g; 80 mM) in isobutanol (250 ral) is reflux heated for 15'. The solvent is evaporated almost completely, by stripping with n-heptane; the residue is taken with ethyl acetate (200 ml), washed with an aqueous solution saturated with sodium bicarbonate up to disappearance of the imidazole, then with water and with an aqueous solution saturated with sodium chloride. It is dehydrated on sodium sulfate and diethyl ether is added. Crystallization gives 3.5 g (6.8 mM) of a white solid. Yield 42.5%, m.p. 157-1580C.

The following derivatives are prepared with the same method: EXAMPLE 7 2-[(p-isobutyloxycarbonyl)-phenoxy3-2-methoxyiimine-propylthio4,5diphenyl imidazo- le From 0-methylhydroxylamine hydrochloride, purification by silica chromatography, eluting with CH2C12/Me0H 503. Yield 73%, m.p. 49-520C.

EXAMPLE 8

2f -C(p-isobutyloxycarbonyl)phenoxy3-2-n-decyloxyimine-propyl-thi4,5diphenyli mida zole 6 From O-decyl hydroxylamine hydrochloride in absolute ethanol at room temperature. Purification by silica chromatography, eluting with CH2Cl2IMeOH 100:1. Yield 63%, oil.

EXAMPLE 9

2-EO-(3-hydroxypropyl)-oxyimine3-3-C(4-isobutyloxycarbonyl)-phenoxy3propyl thii4, -i7 5-diphenyl imidazole. From 0-(3-hydroxypropyl)-hydroxylamine hydrochloride, in absolute ethanol at room temperature. Purification by silica chromatography, eluting with n-hexane/ethyl acetate 7:3. Yield 53%, m.p. 680C. EXAMPLE 10 2-[(p-isobutyloxycarbonyl)-phenoxyj-2hydrazonecarboxamide-propylthii4,5-di phenyI imidazole. From semicarbazide hydrochloride in 95% ethanol/water. Yield 25%, m.p. 172- 1740C. EXAMPLE 11 2- 1 5-[(p-isobutyloxycarbonyl)-phenoxY)-n-pentylthioj - 4,5-diphenyl imidazole A solution of 4,5-diphenylidazole-2-thiol (2.6 g; 10 MM), isobutyl p-(5-bromo)-pentyloxybenzoate (3.5 g; 10 mM) and 2,6- lutidine (2.4 ml; 21 mM) in anhydrous dimethy1formamide (3o ml) is heated to 700C, under nitrogen and stirring, for 24 hours. The solution is cooled and poured in an aqueous solution saturated with sodium carbonate under stirring. The precipitate is filtered, washed with petroleum ether and crystallized from absolute ethanol obtaining 1.84 g (3.5 mM) of a white crystalline solid. Yield 36%, m.p. 123-1230C. The following derivatives are prepared using the same method: EXAMPLE 12 2- 2-[(pisobutyloxycarbonyl)-phenoxY37ethylthio -4,5-diphenyt-imidazole. From isobutyl p-(2-chloro)-ethoxybenzoate. Yield 42%, m.p. 163-1640C EXAMPLE 13 2-[(p-isobutyloxycarbonyl)-phenoxy3-propylthio i -4,5-diphenyl- imidazole. From isobutyl p-(3-bromo)-propyloxybenzoate. Yield 60%, m.p. 154-1550C EXAMPLE 14 2- 1 4-[(p-isobutyloxycarbonyl)-phenoxy3-butylthio) 4,5-diphenyl-imidazole k 7 From isobutyl p-(4-chloro)-butyloxybenzoate. Yield 40%, m.p. 152-1550C EXAMPLE 15 2-J 6-[(p-isobutyloxycarbonayi)-phenoxY]-n-esylthio -4,5-di- phenylimidazole From isobutyl p-(6-bromo)-esyloxybenzoate. Yield 62%, m.p. 135-136,OC EXAMPLE 16 2- 1 S-C(p-isobutyloxycarbonyl)-phenoxyj-n- octylthio 4,5-diphenyl-imidazole From isobutyl p-(S-bromo)- octyloxybenzoate. Yield 35%, m.p. 113-1150C EXAMPLE 17 2- f 10-L(pisobutyloxycarbonyl)-phenoxY3-n-decylthio I -4,5-di-phenylimidazole From isobutyl p-(10-bromo)-decyloxybenzoate. Yield 57%, m.p. 108-1090C EXAMPLE 18 2- 1 12-LI(p-isobutyloxycarbonyl)-phenoxY3-n-dodecylthioJ -4,5-diphenylimidazole From isobutyl p-(12-bromo)dodecyloxybenzoate. Yield 28%, m.p. 900C EXAMPLE 19 2- 5-Li(p-ethoxycarbonyl)phenoxY3 -n-pentylthio I -4, 5-dipheyl-imidazole From ethyl p-(5-bromo)-pentyloxybenzoate. Yield 48%, m.p.1300C EXAMPLE 20 2- 1 5(p-carboxy)-phenoxY3-n-pentylthioI -4,5diphenylimidazole From p-(5-bromo)-pentyloxy benzoic acid. Yield 74%, m.p. 187-1900C The compounds to which the invention refers have been subjected to specific pharmacological screening. ACAT INHIBITORY ACTIVITY IN VITRO The activity of the ACAT enzyme is measured in vitro evaluating the transfer of oleic acid from Coenzyme A to cholesterol, in the process of formation of cholesterol oleate. Endogenous cholesterol, coming from the microsomial fraction, and E14-C]Oleyl-CoA, were used as substrates. The microsomial fraction is prepared from the liver of male SD rats (Charles River), weighing 150-300 g, fed "ad libitum" with normal standard diet. After sacrifice by decapitation, the liver of the animals is removed and homogenized in 2.58 volumes of 0.25 M sucrose buffer containing I mM EDTA (pH 7.4). The microsomes are then obtained by differential centrifugation: the surnatant of an initial centrifugation of 10000 g for 20 minutes (40C) is then 8 centrifuged again in O.IM phosphate buffer (pH 7.4) at 105000 g for I hour in order to sediment the required fraction. The microsomes thus obtained are then suspended again in the same buffer, centrifuged once again and then kept at -800C until used. The test is carried out in test-tubes using a final incubation volume of 200.,ul. To each test-tube are added 100 pl of buffer and 150 mg of microsomial proteins.

The compounds being tested (solubilized in absolute ethanol) and the vehicle (absolute ethanol) are added in volumes not exceeding I I ul.

The test-tubes are then preincubated for 10 minutes at 370C, then added with 100 pl of L14-CD-oleyl-CoA (6.1 uCi, final concentration 50 uM). The incubation is terminated after 10 minutes by adding a mixture (4 ml) of chloroform methanol (2:1 v/v).

To the samples are then added 20000 dpm of L3-H] cholesteryl-oleate as internal standard.

The organic phase, containing the lipids, is separated after having maintained the samples for IS hours at 40C. The samples are dried under nitrogen flow and suspended again in 100,ul of ethyl acetate.

Then 50 Ul are applied to silica gel plates (HPTLC, Merck) and eluted with a mobile phase consisting of hexane:diethyl ether:acetic acid (80:20:1). The band corresponding to cholesterol-oleate is visualized by exposing the plate to iodine vapours.

The band thus identified is scraped off the plate, placed in a vial to which scintillating liquid is added and the sum of the radioactivity is evaluated by means of a liquid scintillator (Beckman).

The basal counts are evaluated by means of control preparations subjected to boiling for 10 minutes.

The percentage inhibition of the ACAT enzyme activity, obtained in the presence of the compounds in question, is calculated percentage-wise compared to the control values.

The control values, determined in the presence of the solubilization vehicle, correspond on an average to 50 nM 'E14-C] formed cholesterol oleate/h/mg microsomial proteins.

9 The inhibitory activity of the ACAT enzyme for the compounds of the invention and for the reference compounds (Ci-976 and RP-70676), is demonstrated in Table I and is expressed as concentration at which the ACAT activity is inhibited by 50% (IC50).

"IN VITRO" INHIBITORY ACAT ACTIVITY ON RAT LIVER MICROSOMES TABLE I example no. I

2 3 4 5 6 7 8 9 11 12 13 14 is 16 17 18 19 20 2.6 2.0 IC50 W) 4.2 6.1 2.7 14.2 18.3 0.4 11.4 >>10 1.8 2.0 1.3 120.0 8.2 1.9 9.2 29.7 422.0 330.0 0.3 3.4 CI-976 RP-70676 HYPOLIPIDAEMIC ACTIVITY IN VIVO The hypolipidaemic activity is evaluated in vivo in rats, using male SD animals (Charles River) initially weighing 130-150 S, housed under controlled conditions with -1 a temperature of 21 IOC. 60% relative humidity and 12 hour light/dark cycles.

The experimental model utilized envisages the use of animals fed "ad libitum" with modified Nath diet (Atherosclerosis, LO, 1978, p.45) having the following composition: hydrogenated coconut oil 24% cholesterol 0.5% cholic acid 0.5% casein and vitamins 21% mineral salts 4% corn oil I % sucrose 48% The animals are fed with this diet for 15 consecutive days, during which they are given the compounds in question once a day by oral route. 24 hours after the last administration, the animals are sacrificed by decapitation removing their blood for the determination of serum lipids and their liver for the evaluation of those in the liver.

This experimental model has the aim of evaluating the efficacy of the products which are most active "in vitro" and most representative of the chemical class, on a consolidated model of hyperlipidaemia as well as of controlling at the same time the efficacy and safety of the compounds in the liver.

The determination of the triglycerides, total cholesterol, associated with the HDL and free cholesterol, is carried out by means of commercially available enzymatic kits.

The concentration of cholesterol VLDL + LDL is determined on the difference between total cholesterol and HDL.

The concentration of cholesterol esterified in the liver is evaluated on the difference between total and free cholesterol. The lipids are extracted according to Folch's method (J.Biol.Chem., 226, 1957, p.497) with a mixture of chloroform:methanol (2:1) after homogenization. The lipids contained in the organic phase are then dried under nitrogen flow, redissolved in isopropanol and evaluated using commercial kits.

The results obtained in the experimental model in vivo for some of the most interesting and representative compounds of the invention are reported in Table 2. The same table reports the data regarding the two reference compounds (CI-976 11 i andRP-70676). The values are expressed as percentual variation compared to the hyperlipidaemic controls which received carboxymethyl-cellulose (CMC) 0.5% in water, at the dose of 10 ml/kg/day by oral route. This same vehicle is used for the suspension of the compounds in question, tested at the doses of 10 and 50 mg/kg/day by oral route. Table 2 SERUM LIVER Example Dose Triglyc. Cholesterol Cholesterol no. mg/kg VLDL +LDL HDL Free Esterif 1 10 -13 -29 +21 -18 -59 -13 -44 +16 10 -15 -6 +6 -33 +4 +2 -22 +7 9 10 -18 -30 +21 -26 -49 so -0 -35 +25 10 +30 -48 +43 -41 -77 so -11 -42 +29 CI-976 10 -6 +1 +6 -14 -19 -20 -20 +10 RP-70676 10 -0 +3 +15 -3 -16 so -26 -34 +37 The compounds of the present invention have a very powerful ACAT inhibitory activity in vitro and a very interesting hypolipidaemic activity in vivo, involving cholesterol as well as serum triglycerides. As regards the activity on cholesterol, these compounds are in fact able to significantly reduce the fraction associated to the VLDL and LDL lipoproteins, while they determine an increase of the fraction bound to the HDL. Also the circulating triglycerides; are reduced, though to a lesser extent. For the use as hypolipidaemic agents, the compounds of the present invention are preferentially administered by oral route. The new compounds can therefore be 12 7-1 presented in the form of capsules, tablets, film coated tablets, powder, oral solutions or liquid suspensions.

All the above mentioned preparations can contain the conventional additives and excipients.

The dosage of the compound to be administered for hypolipidaernic therapy depends on the type of compound used, on the weight, age, sex of the patient, on the particular disease to be treated and also, for this particular type of compound, on the desired therapeutic effect.

Generally the daily dosage can vary between 10 and 1000 mg of active ingredient divided in 1-3 administrations. The compositions will contain generally around 5 to 500 mg of active ingredient per dosage unit.

In conclusion, on the basis of what reported herein, the compounds of the invention by virtue of their inhibitory action on the enzyme acyl-CoA: cholesterol acyl transferase (ACAT), can be hypo-lipidaemic, decreasing the absorption of cholesterol by the intestine as well as the secretion of VLDL lipoproteins by the liver.

Moreover, acting on the enzyme directly on the vasal wall, they can interfere with the accumulation mechanism of cholesterol esters and consequently slow down, block or diminish the processes involved in the development of the atherosclerotic plaque.

These compounds can therefore be used in all the diseases deriving from the presence of an atherosclerotic phenomenon, such as for example stable or unstable angina pectoris, myocardial infarct, cardiac insufficiency, thrombosis, cerebral ischaernia, renal insufficiency and nephrotic syndromes.

c t.

13 1

Claims

CLAIMS 1. Compounds having the general formula (II): Het-S-CH2-Y-CH2-0-R

(II) where: Het - 4,5-diphenylimidazole-2-yl; Y - -CO-; -(CH2)n- where 0<n<10; -C=n-R2 where R2 OH, Cl-Clo,-NHCONH2; R = phenyl substituted in para with a carboxyl or alkoxycarbonyl CI-C20 group where the alkoxy can be linear or branched.
2. Compounds according to claim 1, characterized by being 23-C(p-isobutyloxycarbonyl)-phenoxY3-2-oxo-propylthio -4,5-diphenylidazole 4,5-diphenylimidazole 2 -[(p-isobutyloxycarbonyl)-phenoxy -2-hydroxymine-propylthi 2- -[(pisobutyloxycarbonyl)-phenoxy]-2-methoxymine-propylthi-4,5-diphenylimid azole 2-[(p-isobutyloxycarbonyl)-phenoxy3-2-n-decyloxyimine-propylthi+4,5dupheny limida zol 2--CO-(3-hydroxypropyl)-oxymine]-3-1-(4isobutyloxycarbonyi)-phenox,yj-prop ylthi4,5 -diphenylimidazole 2--(pisobutyloxycarbonyl)-phenoxY3-2-hydrazonecarboxamide-propylthi4,5-d iphenyl imidazole 2- {5-9p-isobutyloxycarbonyl)-phenoxY3-n-pentylthio-4,5diphenylimidazole 2-1 2-[(p-isobutyloxycarbonyl)-phenoxY3-ethylthio3 -4,5diphenyl imidazole 2- {3-1(p-isobutyloxycarbonyl)-phenpxyj-propylthio3 -4, 5-diphenylimidazole 2- 4(p-isobutyloxycarbonyl)-phenoxy3-butylthio -4,5diphenylimidazole 2- 6-C(p-isobutyloxycarbonyl)-phenoxy3-n-esylthio -4,5diphenylimidazole 2- 8-E(p-isobutyloxycarbonyl)-phenoxY]-n-octylthio -4,5diphenylimidazole 2-f 10-C(p-isobutyloxycarbonyl)-phenoxY]-n-decylthio -4, 5-diphenylimidazole 2-1 12-[(p-isobutyloxycarbonyl)-phenoxi-ndodecylthioj -4,5-diphenylimidazole 2- 5-C(p-ethoxycarbonyl)-phenoxy3-npentylthio 1 -4,5-diphenylimidazole 2- 5-U(p-carboxy)-phenoxy]-npentylthio j -4,5-diphenylimidazole
3. Pharmaceutical compositions, characterized by containing as active ingredient a alkoxy Cl-Clo, ornega-hydroxy alkoxy 14 1 compound as in claim 1, together with the usual excipients and vehicles.
4. Pharmaceutical compositions as in claim 3, characterized by the fact that said compound has been chosen from those in claim 2.
5. Use of the compounds having the general formula (11) Het-S-CH2-Y-CH2-0-R (II) where: Het - 4,5-diphenylimidazole-2-yl; Y = -CO-; -(CH2),- where O<n<10; -CHOH-, meaning the racemic mixture as well as each of the two chiral forms; -C - N-R2 where R 2 = OH, alkoxy CI-Clo, omega-hydroxy alkoxy CI- Clo, -NHCONH2; R = phenyl substituted in para with a carboxyl or alkoxycarbonyl Cl-C20 group where the alkoxy can be linear or branched, as ACAT inhibiting agents.
6. Use as in claim 5, characterized by the fact that it is directed at treatment of atherosclerosis, with particular reference to the accumulation of cholesterol and to the development of the atheromasic plaque.