WO1995014673A1

WO1995014673A1 - 4,5-diphenylimidazole derivatives, their preparation and their use as acyl coenzyme a: cholesterol-0-acyl-transferase (acat) inhibitor

Info

Publication number: WO1995014673A1
Application number: PCT/EP1994/003684
Authority: WO
Inventors: Marino Gobetti; Massimiliano Palladino; Ermes Vanotti; Manuela Villa; Massimo Bani; Rita Bormetti; Vincenzo Olgiati
Original assignee: Pharmacia S.P.A.
Priority date: 1993-11-22
Filing date: 1994-11-09
Publication date: 1995-06-01
Also published as: CA2154475A1; ITMI932468A1; AU8061894A; EP0680472A1; JPH08506122A; IT1265209B1; ITMI932468A0

Abstract

The invention provides new diphenylimidazoles of formula (I) wherein: Ph is phenyl; and wherein A) when Z is 4,5-diphenylimidazol-2-ylthio, then p is zero and Y is a --(Ch2)m--X--(CH2)n-- group in which a) m and n being the same are 1 or 2 and X is (1), (2) or (3), wherein R is hydrogen or an optionally omega-hydroxy substituted C1-C10 alkyl chain, or b) m and n are 2 and X is (4), (5), (6) or (7), in which q is 1 or 2; or B) when Z is an aryloxy group unsubstituted or substituted by a substituent chosen from C1-C6 alkyl, halo-C1-C6 alkyl, C1-C6 alcoxy, halogen, amino or an aryloxy group substituted by two substituents chosen from C1-C6 alkyl, halo-C1-C6 alkyl, C1-C6 alkoxy, halogen, amino, nitro, C1-C6 alkoxy-carbonyl, di(C1-C6 alkyl) amino and --NHCONH-C1-C6 alkyl, or an aryloxy or arylthio group substituted by three sustituents chosen independently from hydroxy and C1-C6 alkyl, or a group chosen from 2-pyridyloxy, an optionally substituted imidazo[1,2-b]pyrazol-1-yl group, 2,3--dihydro-1H-imidazo[1,2--b]pyrazol-1-yl and (8) in which R1 is (9), (10) or (11), in which each of R2, R3 and R4 independently is hydrogen, C1-C4 alkyl or C1-C4 alkoxy; then p is zero or 1 and Y is a --(CH2)m--X--(CH2)n-- group wherein m and n are 1, X is a --(CH A)t-- group wherein A is hydrogen or hydroxy and t is zero or an integer of 1 to 10, or a group chosen from (12), (13), (14), (15) in which R is as defined above; or C) when Z is thiazolidin--2,4--dione--5--yl, then p is zero and Y is a bond or a --(CH2)m--X--(CH2)n-- group in which m and n are 1, X is a --(CH2)t-- group in which t is as defined above, and the pharmaceutically acceptable forming salts thereof, which have an ACAT inhibiting activity and are thus useful in the treatment of dyslipidemia, atherosclerosis and coronary diseases.

Description

4, 5-di phenyl imi dazol e deri vati ves , thei r preparati on and thei r use as acyl coenzyme A_: chol esterol -O-acyl -transferase (ACAT) i nhi bi tor

The present invention relates to new diphenylimidazoles having ACAT inhibiting activity , to a process for their preparation and to pharmaceutical compositions containing them. It is well known that high levels of plasma cholesterol represent a primary risk factor in the development of lesions of the arterial wall and induction of atherosclerotic disease .

The cholesterol present in the intestine, contained in the diet or pancreatic juice and bile, to be absorbed, must be first and foremost transported and stored in the intestinal wall as cholesteryl ester. During the process of storage acyl coenzyme A is involved: cholesterol -O-acyl-transferase (ACAT; EC 2.3.1.2.6) which, catalyzing the transfer of a fatty acid from coenzyme A to cholesterol is able to regulate intracellular esterification of cholesterol itself. This enzyme, still not completely purified and characterized, with molecular weight of approximately 180 kDa, plays an important role not only in absorption of exogenous cholesterol in the intestinal district but also in other tissues. In the liver, esterification of cholesterol by ACAT enzyme is strictly necessary for the process of secretion of very low density lipoproteins (VLDL) . In the macrophages ACAT regulates the cellular disposition of cholesterol esters, determining the transformation into foamy cells. Lastly, in muscle cells a high activity of this enzyme can cause lipid engulfment. Therefore, therapeutic agents able to effectively inhibit the action of ACAT can exert a hypolipidemic effect, preventing absorption of cholesterol present in the intestine as well as its secretion by the liver. In addition, it has been demonstrated that during the atherosclerotic process the activity of this enzyme is greatly enhanced, with accumulation of cholesterol esters at the intestinal wall. Consequently, an inhibitor of this enzyme can be actively used in atherosclerotic disease. Thus, compounds provided with ACAT inhibitory activity, besides possessing hypolipidemic activity are also antiatherosclerotic agents aimed in interfering with the accumulation of cholesterol esters and development of the atheromasic plaque. Such agents prove to be therefore useful in the prevention of various coronary and vascular diseases, such as myocardial infarction and angina. Several diphenylimidazoles are known in the art. For instance, EP-391796 and WO 9110662 disclose diphenylimidazoles having anti-hyperlipidae ic and/or anti¬ atherosclerotic activity. The 2-substituted-4,5- diphenylimidazole derivatives disclosed by U.S. 4,190,666 are useful as anti-inflammatory, immunoregulatory and analgesic agents. Similarly, analgesic activity is described for the compounds claimed by BE-871168.

The present invention provides compounds having the following formula (I)

wherein

Ph is phenyl; p is zero or 1;

Y is a bond or a—(CH₂)_m—X—(CH₂)_n— group, wherein m and n being the same are 1 or 2 and X is a—(CH A) ^■— group wherein A is hydrogen or hydroxy and t is zero or an integer of 1 to

10, or a group chosen from CO, C=NOR wherein R is hydrogen or an optionally omega-hydroxy substituted C,-C₁₀ alkyl chain,

Z is a group selected from 4,5-diphenylimidazol-2-ylthio; an aryloxy group unsubstituted or onosubstituted by a substituent chosen independently from C]-C₆ alkyl, halo-C,- C₆ alkyl C,-C₆ alkoxy, halogen, amino and nitro; an aryloxy group substituted by two substituents chosen independently from C,-C₆ alkyl, halo-C,-C₆ alkyl, C,-C₆ alkoxy, halogen, amino, nitro, C,-C₆ alkoxy-carbonyl, di(C,-C₆ alkyl) amino and -NHCONH-C,-C₆ alkyl; an aryloxy or arylthio group substituted by three substituents chosen independently from hydroxy and C,-C₆ alkyl;

2-pyridyloxy; an optionally substituted imidazo[l,2- b]pyrazol-l-yl group; 2, 3-dihydro-lH-imidazo[1,2- b]pyrazol-l-yl; thiazolidyn-2,4-dione-5-yl;

in which each of R₂, R₃ and R₄ independently is hydrogen, C,-C₄ alkyl or C,-C₄ alkoxy; and the pharmaceutically acceptable forming salts thereof, and wherein

A) when Z is 4, 5-diphenylimidazol-2-ylthio, then p is zero and Y is a—(CH₂) . -—. X—(CH₂)_n — group in which a) m and n being the same are 1 or 2 and X is or

wherein R is as defined above, or b) m and n are 2 and X is

in which q is 1 or 2 ; or

B) when Z is an aryloxy group unsubstituted or substituted by a substituent chosen from C,-C₆ alkyl, halo—C,-C₆ alkyl, C,-C₆ alkoxy, halogen, amino or an aryloxy group substituted by two substituents chosen from C,-C₆ alkyl, halo-C,-C₆ alkyl, C,-C₆ alkoxy, halogen, amino, nitro, C_!-C₆ alkoxy-carbonyl, di(C,-C₆ alkyl) amino and -^IHC0NH-C₁-C₆ alkyl, or an aryloxy or arylthio group substituted by three substituents chosen independently from hydroxy and C,-C₆ alkyl, or a group chosen from 2—pyridyloxy, an optionally substituted imidazo[l,2- b]pyrazol-l-yl group, 2 , 3—dihydro-lH-imidazo[1,2—

b]pyrazol-l-y

are as defined above, then p is zero or 1 and Y is a—(CH₂)_m—X—(CH₂)_n — group wherein m and n are 1, X is a—(CH A)_t— group wherein A and t are as defined above, or a group chosen from -CO—, in

which R is as defined above; or

C) when Z is thiazolidin—2 ,4—dione—5—yl, then p is zero and Y is a bond or a—(CH₂)_m—X—(CH₂J_n— group in which m and n are 1, X is a—(CH₂)— group in which t is as defined above.

The invention includes within its scope all the possible isomers, stereoisomers, and their mixtures and the metabolites and the metabolic precursors or bio-precursors of the compounds of formula (I) .

The alkyl, alkoxy, di-alkylamino and haloalkyl, hydroxy- alkyl, ureido-alkyl and alkoxy-carbonyl groups may be branched or straight chain groups.

A-(CH₂)_m—, —(CH₂)_n—, —(CHA)j- or —(CH₂),— group, when m, n or t, respectively, is an integer higher than 1 can provide independently a branched or straight alkylene chain.

A C_!-C_I0 alkyl chain is preferably a C]-C₆ alkyl chain, typically methyl, ethyl, propyl, isopropyl, butyl and tert- butyl.

A C,-C₆ alkyl group is e.g. a C,-C₄ alkyl group, in particular methyl, ethyl, propyl or butyl.

A C,-C₄ alkyl is typically methyl, ethyl, propyl, isopropyl, butyl and tert-butyl.

A halo—C,-C₆ alkyl group is e.g. a halo—, dihalo— or trihalo—alkyl, in which the halogen atom is e.g. chlorine, bromine or fluorine, preferably it is a halo—C,-C₄ alkyl, typically trifluoromethyl. A C,-C₆ alkoxy is preferably methoxy, ethoxy, propoxy, isopropoxy, in particular methoxy or ethoxy.

A C,-C₄ alkoxy is typically methoxy, ethoxy, propoxy, isopropoxy, butoxy and tert-butoxy.

A halogen atom is e.g. chlorine, bromine or fluorine, in particular chlorine or fluorine, typically fluorine.

An aryloxy group is e.g. a naphthyl-oxy or phenoxy group, preferably a phenoxy group.

An arylthio is e.g. a naphthyl-thio or phenylthio group, preferably a phenyl-thio group. An imidazo[l,2-b]pyrazol-l-yl group when substituted is typically substituted by one or two substituents at the 2,3 and/or 6 positions, the substituent being preferably a phenyl group.

A C,-C₆ alkoxy-carbonyl group is preferably a Cj- alkoxy- carbonyl group, wherein the C,-C₄ alkoxy moiety is typically as defined above.

A di(C_!-C₆ alkyl) amino group is preferably a di(C,-C₄ alkyl) amino group, in particular dimethylamino and diethylamino. Pharmaceutically acceptable salts of the compounds of the invention include acid addition salts, with inorganic, e.g. nitric, hydrochloric, hydrobromic, sulfuric, perchloric and phosphoric acids, or organic, e.g. acetic, propionic, glycolic, lactic, oxalic, malonic, malic, maleic, tartaric, citric, benzoic, cinnamic, mandelic and salicylic acids. As stated above, the present invention also includes within its scope pharmaceutically acceptable bio-precursors (otherwise known as pro-drug) of the compounds of formula (I) , i.e. compounds which have a different formula to formula (I) above but which converted directly or indirectly in-vivo into a compound of formula (I) .

Preferred compounds of the invention are the compounds of formula (I) , wherein subject to the above proviso Ph is phenyl; p is zero or 1; Y is a bond or a—(CH₂),,—X—(CH₂)_n— group, wherein each of m and n is 1 or 2 and X is a group —(CHA)_t— wherein A is as defined above and t is zero or an integer of 1 group in which R is as defined above, or

Z is a group selected from

4 ,5-diphenylimidazol-2-ylthio; a phenoxy group unsubstituted or substituted by a substituent independently chosen from halogen, 0,-0₄ alkyl, C[-C₄ alkoxy, trifluoromethyl and nitro; a phenoxy group substituted by two substituents independently chosen from halogen, C,-C₄ alkyl, Cι-C₄ alkoxy, trifluoromethyl, nitro, di(C,-C₄ alkyl) amino, C,-C₄ alkoxy-carbonyl and — HCONH-Cj-Cβ alkyl; a phenoxy or phenylthio group substituted by three substituents independently chosen from hydroxy and C,-C₄ alkyl;

2-pyridyloxy; imidazo[1,2-b]pyrazol-l-yl unsubstituted or substituted by one or two phenyl groups; thiazolidyn-2,4- R,

dione-5-yl; and an group wherein R_x is as

defined above; and the pharmaceutically acceptable salts thereof.

More preferred compounds of the invention are the compounds of formula (I) wherein Ph is phenyl; p is zero;

Z is 4,5-diphenylimidazol-2-ylthio;

Y is a—(CH₂) wherein m and n are as defined above and X R is hydrogen or C,-C₆ alkyl,

; and the pharmaceutically acceptable

salts thereof.

More preferred compounds of the invention are also the compounds of formula (I) wherein Ph is phenyl; p is zero or 1; Z is a group selected from: a phenoxy group substituted by a substituent chosen from halogen, C^-O.^ alkyl, C,-C₄ alkoxy, trifluoromethyl and nitro; a phenoxy group substituted by two substituents independently chosen from halogen, C,-C₄ alkyl, C,-C₄ alkoxy, C,-C₄ alkoxy-carbonyl, di(C,-C₄ alkyl)amino, and

--NHCONH-C,-^ alkyl; a phenoxy or phenyl-thio group substituted by three substituents independently chosen from hydroxy and C,-C₄ alkyl;

group

independently hydrogen, C,-C₄ alkyl or C,-C₄ alkoxy; and Y is a—(CH₂)_m—X—(CH₂)_n— group wherein m and n are as defined above and X is —(CHA)_t— in which t is zero or an integer of 1 to 4 and A is as defined above; and the pharmaceutically acceptable salts thereof.

More preferred compounds of the invention are also the compounds of formula (I) wherein

Ph is phenyl; p is zero;

Z is thiazolidin—2,4—dione—5—yl; and Y is a bond or a—(CH₂)_m—X—(CH₂)_n— group wherein m and n are as defined above and X is —(CH₂)_t— in which t is an integer of 1 to 4; and the pharmaceutically acceptable salts thereof.

Examples of preferred compounds of the invention are the following, herebelow numbered according to the relevant occurring experimental preparation example: 1) 2-oxyimino-l,3-bis-(4 , 5-diphenylimidazole-2-ylthio) - propane;

2) 3-oxyimino-l, 5-bis- (4 , 5-diphenylimidazole-2-ylthio) - pentane; 3) 2-hydrazonecarboxyamide-l, 3-bis- (4 , 5-diphenylimidazole- 2-ylthio) -propane;

5) 2-(0-pentyloxyimino) -1 , 3-bis-(4 , 5-diphenylimidazole-2-yl thio) -propane;

6) 2-0- (3-hydroxypropyl) -oxyimino-1, 3-bis- (4 , 5-diphenyl- imidazole-2-yl-thio) -propane;

7) 2-{3-[p- (2 , 6-diisopropylphenylcarboxamido)phenoxy] propylthio}-4 , 5-diphenylimidazole;

8) 2-{5-[p- (2 , 6-diisopropylphenylcarboxyamido) phenoxy] pentylthio}-4 , 5-diphenylimidazole; 9) 2-{5-[p- (2 , 4 , 6-trimethoxyphenylcarboxamido)phenoxy] pentylthio}-4 , 5-diphenylimidazole;

10) 2-[3-(imidazo[l,2-b]pyrazol-l-yl)propylthio]-4, 5- diphenyli idazole;

11) 2-[5-(imidazo[l, 2-b]pyrazol-l-yl) pentylthio] -4 , 5- diphenylimidazole;

13) 2-[3-(6-phenyl-imidazo[1, 2-b]pyrazol-1-yl) propylthio] -4 , 5-diphenylimidazole;

14) 2-[3- (2 , 4-difluorophenoxy) propylthio]-4 , 5-diphenyl- imidazole; 15) 2-[5-(2 , 4-difluorophenoxy)pentylthio]-4,5-diphenyl- imidazole; 16) 2-[5- (4-fluorophenoxy)pentylthio]-4 , 5-diphenylimidazole;

18) 2-[3- (4-methylphenoxy)propylthio] -4 , 5-diphenylimidazole;

19) 2-[3- (2 , 5-dimethylphenoxy) propylthio]-4 , 5-diphenyl- imidazole;

20) 2-[5- (2 , 5-dimethylphenoxy)pentylthio]-4 , 5-diphenyl- imidazole;

21) 2-[5- (2 , 3 , 5-trimethylphenoxy)pentylthio]-4 , 5-diphenyl- imidazole; 22) 2-[5- (4-methoxyphenoxy) pentylthio] -4 , 5-diphenyl- imidazole; 23) 2-[5-(3-methoxyphenoxy)pentylthio]-4, 5-diphenyl- imidazole;

25) 2-[5-(4-chlorophenoxy)pentylthio]-4,5-diphenylimidazole;

26) 2-[5-(3-trifluoromethylphenoxy)pentylthio]-4 , 5-diphenyl- imidazole;

27) 2-[5-(4-terbutylphenoxy)pentylthio]-4,5-diphenyl- imidazole;

28) 2-[5-(4-nitrophenoxy)pentylthio]-4,5-diphenylimidazole;

29) 2-{5-[ (2-methoxy,4-methoxycarbonyl)phenoxy]pentylthio}- 4, 5-diphenylimidazole;

30) 2-[5-(2-pyridoxy)pentylthio]-4 , 5-diphenylimidazole;

31) 2-[5-(3 , 5-diterbuty1,4-hydroxyphenylthio)pentylthio]- , 5-diphenylimidazole;

32) 2-[5-(2-butylureido, 3-dimethylaminophenoxy)propylthio]- 4, 5-diphenylimidazole;

33) 2-[3-(2,4-difluorophenoxy) -2-hydroxy propylthio]-4,5- diphenylimidazole;

34) 5-(4,5-diphenyl-imidazole-2-yl-thio) -thiazolidine-2 ,4- dione; 35) 5-[3-(4, 5-diphenylimidazole-2-ylthio)propyl]- thiazolidine-2 , 4-dione;

36) 5-{4-[2-(4, 5-diphenylimidazole-2-ylthio) -ethoxy]benzyl}- thiazolidine-2,4-dione;

37) 5-{4-[2-(4, 5-diphenylimidazole-2-ylthio) -ethoxy) benzyl- idene}-thiazolidine-2,4-dione;

38) 2-[5-(imidazo[1,2-b]pyrazol-1-yl)pentylsulfinyl]-4,5- diphenylimidazole; and

39) 3-(l, 3-dioxolan-2-yl) -1, 5-bis-(4, 5-diphenylimidazole-2- ylthio)pentane, if the case either as single isomers or as a mixture of isomers thereof, and the pharmaceutically acceptable forming salts thereof.

The compounds of the invention and the salts thereof can be obtained by a process comprising:

a) reacting a 4 , 5-diphenylimidazole-2-thiol compound of formula (II )

in which Ph is phenyl, with a compound of formula (III)

Hal-(CH₂)_m-X-(CH₂)-Z (III)

wherein

Hal is halogen, m, n, X and Z are as defined above, thus obtaining a compound of the invention wherein p is zero; or

b) reacting a compound of formula (IV)

wherein

Ph, m, n, p and Z are as defined above, with a compound selected from the group (V) consisting of

H₂N-OR

H₂N-*NHCONH₂ (V)

H₂N-NHCSNH₂ wherein R is as defined above, thus obtaining a compound of formula (I) wherein Y is a group —-(CH₂)_n—X—(CH₂)_m—- in which X is respectively,

and m, n and R are as defined above; or

c) reacting a compound of formula (II) as defined above with an epoxide of formula (VI)

CH₂-CH-CH₂—Z (VI) wherein Z is as defined above, thus obtaining a compound of the invention wherein p is zero and Y is a group

d) reacting a compound of formula (II) as defined above with a compound of formula (VII)

W-(CH₂)_m-X-(CH₂)_n-W (VII) wherein W is an activated derivative of an hydroxy group and m, n, and X are as defined above, thus obtaining a compound of the invention wherein Z is 4, 5-diphenylimidazol-2-ylthio; or

e) oxidizing a compound of formula (VIII)

wherein

Ph, Y and Z are as defined above, thus obtaining a compound of formula (I) wherein p is 1; and, if desired, converting a compound of formula (I) into another compound of formula (I) , and/or resolving a mixture of isomers of a compound of formula (I) into the single isomers, and/or converting a compound of formula (I) into a pharmaceutically acceptable salt thereof.

Hal in a compound of formula (III) is a chlorine, bromine or iodine atom, preferably a bromine atom.

The reaction of a compound of formula (II) with a compound of formula (III) or of formula (VI) can be carried out in the presence of polar, organic, protic or aprotic solvents_^e.g. a C,-C₄ alkanol, dimetylformamide and dimethylsulfoxide, preferably in the presence of a basic catalyst, substantially belonging to the class of sterically hindered tertiary amines, such as trialkylamine, 2,6-lutidine and pyridine. The reaction is preferably carried out at room temperature, even if sometimes it is more convenient to heat it, to accelerate the course, at a temperature ranging between room temperature and 100°C and preferably at reflux temperature of a lower alcohol, such as ethanol and isopropanol. The reaction is generally complete after a period of time which may vary from 1 to 24 hours according to the substrate and catalyst used. At the end of the reaction, the crystallized product is filtered off or the solvent removed and the residue purified according to the traditional methods of crystallization using appropriate solvents or by chromatography.

The reaction of compound of formula (IV) with a compound selected from the group (V) , as defined above, can be carried out according to known methods. For instance, by reacting the appropriate hydroxylamine compound or εmicarbazide in a protic solvent e.g. water or C,-C₄ alkanol at room temperature.

W as an activated derivative of an hydroxy group is e.g. a mesyloxy or tosyloxy group.

The reaction of a compound of formula (II) with a compound of formula (VII) is an analogy process that can be performed according to known methods. For instance, when W is a tosyloxy group the reaction can be performed in a protic solvent e.g. a lower alkanol, typically C,-C₄ alkanol, in the presence of a basic agent e.g. 2,6-lutidine, at reflux temperature.

Also oxidation of a compound of formula (VIII) to obtain a compound of formula (I) in which p is 1 is an analogy process. Said oxidation is preferably carried out by reaction with a suitable oxidizing agent e.g. m-chloro- perbenzoic acid, in an inert organic solvent e.g. dichloromethane, under cooling.

The optional conversion of a compound of formula (I) into another compound of formula (I) , as well as the separation of a mixture of isomers of a compound of the invention into the single isomers, or the conversion of a compound of formula (I) into a pharmaceutically acceptable salt thereof, can be carried out according to well known methods in the art. Examples of conversion of a compound of formula (I) into another compound of formula (I) are for instance the conversion of an nitro-derivative into the respective amino- derivative and the conversion of an amino-derivative into the respective di (alkyl) amino-derivative. The intermediate compounds of formula (II) , (III) , (V) , (VI) and (VII) are known products or can be obtained according to known methods from known compounds.

For instance the compounds of formula (III) can be obtained respectively, by reaction of the appropriate hydroxyaryl, arylmercaptan, 2-hydroxypyridine, or imidazo[1,2-b]pyrazol with epichlorohydrin or chiral glycidyl tosylates or with a suitable alpha-omega-dihaloalkane. The haloketones are obtained by proceeding via epoxide, opening the haloidric acid and subsequent oxidation of the hydroxy group to carbonyl.

In particular, a compound of formula (III) in which X is —(CH₂)_t— wherein t is as defined above can be prepared from diethylmalonate via alkylation with a compound of formula

Hal-CH₂-(CH₂)..-CHr-B, in which Hal and n are as defined above in the presence of sodium hydride at room temperature in anhydrous tetrahydrofuran; chlorination of the alpha carbon atom at the ester functions with εulfuryl chloride at 70°C; decarboxylation and hydrolysis of the ester functions in the presence of glacial acetic acid and 37% HC1 at reflux; reaction of the resulting alpha-chloro acid with thiourea in 2-methoxyethanol at reflux and treatment with 2N HC1.

The compounds of formula (IV) are compounds of formula (I) according to the present invention wherein Y is a

—(CH₂)_m—X—(CH₂)_n— group in which X is /CO. The compounds of formula (IV) wherein p is zero can be obtained for instance by reaction of a compound of formula

(II) as defined above with a compound of formula (III) wherein X is /CO, as described above.

The compounds of formula (IV) wherein p is one can be obtained for example by oxidation of a compound of formula

(IV) wherein p is zero, as described above as to oxidation of a compound of formula (VIII) .

The compounds of formula (VIII) are compounds of formula (I) in which p is zero. A compound of formula (VIII) can be obtained according to anyone of processes a) , b) , c) and d) described above.

When in the compounds of the invention and intermediate thereof, groups are present which need to be protected before submitting them to the above-described reactions, such group can be protected according to known methods in organic chemistry, and then deprotected at the end of the reaction according to known methods.

PHARMACOLOGY

The compounds of the invention show inhibitory activity of the enzyme acyl CoA: cholesterol acyltransferase (ACAT-EC

2.3.1.26) which regulates the intracellular esterification of cholesterol (Suckling K.E., Stange E.F., J. Lip. Res. (1985) 26. 647) and thus the intracellular accumulation of cholesteryl esters. By virtue of their ACAT inhibitory activity the compounds of this invention, besides having antidyslipidaemic activity, act also as direct antiatherosclerotic agents, able to inhibit the development of the atheromatous plaque, and therefore are useful in particular for the prevention of coronary heart disease (CHD) , e.g. myocardial infarction, angina and cardiac insufficiency, thrombosis, cerebral ischemia, renal insufficiency and nephrotic syndromes. The activity of the enzyme and its regulation by the compounds of the invention has been evaluated in our laboratories both in-vitro and in-vivo tests, for instance as described herebelow.

In-vitro test

The activity of the ACAT enzyme was measured in-vitro evaluating the transfer of oleic acid from coenzyme A to cholesterol, during the process of formation of cholesterol oleate. As substrates, endogenous cholesterol, deriving from the microsomial fraction and [14-C]-oleoyl-CoA. were used. The microsomial fraction was prepared from the liver of SD male rats (Charles River) , weighing 150-300 g, fed "ad libitum" with a normal standard diet. The rats were killed by decapitation and the liver of the animals removed and homogenized in 2.5 volumes of 0.25 M sucrose buffer containing ImM EDTA (pH 7.4) . The icrosomes were then obtained by differential centrifugation: the supernatant of an initial centrifugation at 10000 x g for 20 minutes (4°C) was centrifuged again in 0.1 M phosphate buffer (pH 7.4) at 105000 x g for 1 hour in order to sediment the required fraction. The microsomes thus obtained were resuspended in the same buffer, centrifuged again and maintained at -80°C until ready for use.

The test was carried out in test tubes using a final incubation volume of 200 μl.

To each test tube 100 μl of buffer and 150 μg of microsomial proteins were added. The compounds under study (dissolved in absolute ethanol) and the vehicle (absolute ethanol) were added in a volume not exceeding 1 μl.

The test tubes were preincubated for 10 minutes at 37° C and successively 100 μl of [14-C]oleoyl-CoA (0.1 mCi, final concentration 50 μM) were added. The incubation was stopped after 10 minutes by the addition of a mixture of (4 ml) of chloroform : ethanol (2:1 v/v) .

To the samples 20000 dpm of [3-H]cholesteryl-oleate were added as internal standard. The organic layer, containing the lipids was separated after maintaining the samples at 4°C for 18 hours. The samples were dried under a stream of nitrogen and resuspended in 100 μl of ethyl acetate. Lastly, 50 μl were 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 was visualized by exposing the plate to I vapours.

The band thus visualized was scraped from the plate and placed in a vial to which scintillation liquid was added. The total radioactivity was evaluated by means of liquid scintillation counter (Beckman) .

The background counts were evaluated by preparing controls submitted to 10 minutes boiling. The inhibitory percentage of the activity of the ACAT enzyme obtained in the presence of the compounds under study was calculated in terms of percentage compared to control values. The control values, determined in the presence of the dissolution vehicle correspond on average to 50 nmol [14-C] cholesterol oleate formiate/h/mg of microsomial protein. The inhibitory efficacy of the ACAT enzyme for the compounds representative of the invention and for the reference ones (CI-976 and RP-70676) is shown in Table 1 and is expressed as the concentration at which the ACAT activity is inhibited by 50% (IC₅₀) . TABLE 1 "In-vitro" INHIBITORY ACTIVITY ON RAT LIVER MICROSOMES

Example No. IC_?(1(μM) 1 0.8

2 3.4

3 1.2

4 16.0

5 0.5 6 5.6

7 1.0

8 10.8

9 1.2

10 1.6 11 3.3

12 5.6

13 6.2

14 2.0

15 3.8 16 2.6

17 10.1

18 2.2

19 1.6

20 3.4 21 7.8

22 0.8

23 12.3

24 7.8

25 1.6 26 1.8

27 0.2

28 1.3

29 5.6

30 6.6 31 0.7

32 4.5 TABLE 1 - cont'd - "In-vitro" INHIBITORY ACTIVITY ON RAT LIVER MICROSOMES

Example No. I&otμ )

33 4.0 34 53.0 35 1.5 36 5.6 37 0.9

38 3.5 37 0.9 38 3.5 39 3.2

CI- -976 2.6

RP- -70676 2.0

In-vivo test

Male Sprague-Dawley rats (Charles River, Calco, Italy) , weighing 120-180 g, 8 per group, maintained at 22+l°C temperature and 65+10% relative humidity, were fed ad libitum with a modified Nath's diet supplemented with 1% cholesterol (w/w) , 1 % cholic acid (w/w) (Dottor Piccioni, Gessate, Italy) for 5 days, concomitantly with test compound administration. Test compounds were suspended in 0.5% w/v carboxymethylcellulose and administered daily by gavage between 9-11 a.m. On the fifth day, 2 hours after the last treatment, the rats were exsanguinated by decapitation and blood samples collected. The following analyses were performed on serum obtained by low speed centrifugation:

1) triglycerides and total cholesterol were determined by an enzymatic method (Poli kit) ,

2) HDL cholesterol was determined by an enzymatic method after removal of VLDL+LDL by precipitation (phosphotungstate method) , 3) VLDL+LDL cholesterol was evaluated as difference between total and HDL associated cholesterol. Table 2 summarizes the test data obtained for a representative group of compounds of the invention.

TABLE 2 "In-vivo" 5-day test - dose: 10 mg/kg/day

Example No . % change (vs control) in:

Triglycerides VLDL+LDL HDL cholesterol cholesterol

1 -29+/-2 -42+/-3 +22+/-6

2 -22+/-3 -39+/-2 +27+/-4

3 -16+/-4 -24+/-7 +25+/-1

6 -4+/-5 -10+/-3 +3+/-5

7 -17+/-4 -34+/-3 +7+/-2

8 -11+/-1 -20+/-2 +11+/-1

9 -20+/-3 -18+/-4 +45+/-8

10 -20+/-1 -28+/-4 +12+/-4

11 -27+/-4 -32+/-6 +39+/-3

13 -34+/-3 -32+/-3 +41+/-1

15 -24+/-3 -10+/-3 +22+/-5

16 -18+/-2 -13+/-3 +10+/-5

22 -16+/-3 -24+/-3 +4+/-3

23 -22+/-3 -10+/-1 +12+/-5

26 -39+/-5 -15+/-3 +4+/-1

27 -24+/-1 -11+/-3 +9+/-1

28 -19+/-1 -22+/-3 +1+/-3

29 -17+/-3 -17+/-3 -17+/-3

30 -29+/-6 -37+/-4 +17+/-1

31 -27+/-4 -18+/-1 +11+/-2

34 -15+/-1 -8+/-1 +4+/-3

35 -36+/-1 -32+/-4 +29+/-1

37 -30+/-3 -39+/-1 +11+/-1

38 -17+/-1 -16+/-1 +35+/-8

CI-976 +4+/-3 -4+/-1 +8+/-3

RP-70676 -6+/-3 -25+/-3 +3+/-6

CONTROL VALUES (± SE) Triglycerides 483±10 mg/dl VLDL+LDL chol. 237±7 mg/dl HDL chol. 24±3 mg/dl

NEFA 2150±175 μEq/1

In the tables the compounds of the invention are identified by the relevant preparation example occurring numbers. Reference prior-art compound RP-70676 is 2-[5-(3,5- dimethylpyrazol-1-yl)penthylthio]-4, 5-diphenylimidazole and is disclosed by WO 9110662. Reference compound CI-976 is 2,2- dimethy1-N-(2,4, 6-trimethoxypheny1)dodecanamide and is know from EP-283742.

From the activity test data set out in the above tables it can be appreciated that the in-vitro activity endowed by the compounds of the instant invention is in general substantially comparable to or higher than that shown by the reference compounds; whereas when tested in-vivo the new compounds of this invention have higher activity than that of both the reference compounds. Therefore, the compounds of this invention have more valuable properties as therapeutic agents.

The dosage level suitable for oral administration to adult humans of the compounds of the invention may range from about 10 mg to about 1000 mg per dose 1 to 3 times a day, depending on the disease, age and weight of the patients involved. For example, 2-[5- (4-terbutylphenoxy)pentylthio]-4, 5-diphenyl imidazole and 2-oxyimino-l, 3-bis-(4,5-diphenylimidazole-2-yl thio)propane can be suitably administered orally at a dose in this range.

The toxicity of the compounds of the invention is negligible, therefore they can be safely used in therapy. The compounds of the invention can be administered in a variety of dosage forms, e.g. orally, in the form of tablets, capsules, sugar- or film-coated tablets, liquid solution or suspension.

The invention includes pharmaceutical compositions comprising a compound of the invention in association with a pharmaceutically acceptable excipient (which can be a carrier or diluent) .

The pharmaceutical composition comprising the compounds of the invention are typically prepared following conventional methods and are administered in a pharmaceutically suitable form.

For example, the solid oral forms may comprise, together with the active compound, diluents, e.g. lactose, dextrose, saccharose, cellulose, corn starch or potato starch; lubricants, e.g. silica, talc, stearic acid, magnesium or calcium stearate, and/or polyethylene glycols; binding agents, e.g. starches, arabic gums, gelatin, methylcellulose, carboxymethylcellulose or polyvinyl pyrrolidone; desegregating agents, e.g. starch, alginic acid, alginates or sodium starch glycolate; effervescing mixtures; dyestuffs; sweeteners; wetting agents, such as lecithin, polysorbates, laurylsulphates; and, in general, non-toxic and pharmacologically inactive substances used in pharmaceutical formulations.

Said pharmaceutical preparations may be manufactured in known manner, for example, by means of mixing, granulating, tabletting, sugar-coating, or film-coating processes. The liquid dispersions for oral administration may be e.g. syrups, emulsions, and suspensions.

The syrups may contain as carrier, for example, saccharose or saccharose with glycerine and/or mannitol and /or sorbitol; in particular a syrup to be administered to diabetic patients can contain as carriers only products not metabolizable to glucose, or metabolizable in very small amount to glucose, for example sorbitol.

The suspensions and the emulsions may contain as carrier, for example, a natural gum, agar, sodium alginate, pectin, methylcellulose, carboxymethylcellulose, or polyvinyl alcohol. The following examples illustrate but do not limit the invention:

EXAMPLE 1

2-oxyimino-l.3-bis-(4 , 5-diphenylimidazole-2-yl-thio) -propane

Z = 4,5-diphenylimidazole-2-thio m = n = 1 p = 0

2-oxo-l, 3-bis-(4 , 5-diphenylimidazole-2-yl-thio) -propane (500 mg, 0.89 mmol) and hydroxylamine hydrochloride (310 mg, 4.48 mmol) are dissolved in isobuthanol (50 ml) . The solution is stirred at room temperature until precipitation of a white solid. It is stirred for a further 30', then the solvent is evaporated. The crude substance is taken up with ethyl acetate, the organic solution is washed with saturated NaHC0₃ solution, with water, dried over Na₂S0₄ and concentrated to a solid which is crystallized from diethyl ether, obtaining 330 mg (0.58 mmol, yield 64%) of white product, m.p. 147-149°C.

EXAMPLE 2 Analogously, to example 1 prepare

3-oxyimino-l, 5-bis-(4 , 5-diphenylimidazole-2-yl-thio) - pentane

Z = 4,5-diphenylimidazole-2-thio m = n = 2 p = 0 from 3-oxo-l, 5-bis- (4 ,5-diphenylimidazole-2-yl-thio)pentane. Yield 78%, m.p. 136-138°C.

EXAMPLE 3

2-hvdrazonecarboxyamide-l , 3-bis-(4 , 5-diphenylimidazole-2-yl- thio) -propane

Z = 4, 5-diphenylimidazole-2-thio m = n = 1 p = 0 To a suspension of 2-oxo-l, 3-bis-(4 , 5-diphenylimidazole- 2-yl-thio) -propane (500 mg , 0.89 mmol) in absolute ethanol (10 ml) semicarbazide hydrochloride (100 mg, 0.89 mmol) is added and the solution stirred at ambient temperature for 30 minutes. The organic phase is washed with a saturated solution of NaHC0₃, with water, dried over Na₂S0₄ and concentrated to a solid which is crystallized from diethyl ether. 500 mg of white product are obtained (0.81 mmol, 91% yield) , m.p. 165-167°C.

EXAMPLE 4 2-(O-decyloxyimino) -1, 3-bis-(4 , 5-diphenylimidazole-2- yl-thio) -propane

Z = 4, 5-diphenylimidazole-2-thio m = n = 1 p = 0

2-oxo-l, 3-bis-(4 , 5-diphenylimidazole-2-yl-thio) -propane (500 mg, 0.89 mmol) is suspended in absolute ethanol (15 ml) . O-Decyl- hydroxylamine (190 mg, 0.89 mmol) is added and the solution stirred at ambient temperature until limpid. The solvent is evaporated and the residue taken up with dichloromethane. The organic layer is washed with a saturated solution of NaHC0₃, with water, dried over Na₂S0₄ and concentrated to a solid which is crystallized from diethyl ether obtaining 400 mg of white product (0.53 mmol, 60% yield) . m.p. 178-181°C.

Proceeding with the same working modality the following derivatives are prepared: EXAMPLE 5

2-(O-pentyloxyimino-1, 3-bis-(4 , 5-diphenylimidazole-2-ylthio) propane

Z = 4,5-diphenylimidazole-2-thio m = n = 1 p = 0

From O-pentyl-hydroxylamine hydrochloride, yield 54%, m.p. 211- 215°C.

EXAMPLE 6

2-Q-(3-hydroxypropyl) -oxyimino-1, -bis-(4 , 5-diphenyl- imidazole-2-yl-thio) -propane

Z = 4,5-diphenylimidazole-2-thio m ^*= n = 1 p = 0

From O-(3-hydroxypropyl) -hydroxylamine hydrochloride, yield 87%, m.p. 158-162°C.

EXAMPLE 7 2-{3-fp- ( 2 , 6-diisopropγlphenylcarboxyamido)phenoxy1 propylthio}-4 , 5-diphenylimidazole

To a suspension of 4 ,5-diphenylimidazole-2-thiol (194 mg, 0.77 mmol) in absolute ethanol (10 ml) in reflux,

2,6-lutidine is added (0.1 ml, 0.9 mmol) and then a solution of 3-[p-(2, 6-diisopropylphenylcarboxamido) phenoxy]-1-bromo propane (350 mg, 0.77 mmol) in absolute ethanol (10 ml) is added dropwise. The mixture is refluxed for 24 hours. Then filtered hot over dicalite and concentrated to dryness. The residue is taken up with ethyl acetate and water. The organic layer is washed several times with water, dried over Na₂S0₄ and concentrated. The crude substance is crystallized from ethyl acetate/acetone (1:1), obtaining 270 mg (0.43 mmol, yield 56%) . m.p. > 235°C.

Proceeding with the same working modality the following derivatives are prepared:

EXAMPLE 8

2-15-fp- ( 2 , 6-diisopropylphenylcarboxyamido) henoxy] pentylthio -4 , 5-diphenylimidazole

From 5-[p-(2 , 6-diisopropylphenylcarboxamido)phenoxy] -1-bromo pentane, after purification on silica (eluent n-hexane/acetone 9:1) . Yield 63%, m.p. 180-185°C.

EXAMPLE 9

2- 5-fp- ( 2 i4 , 6-trimethoxyphenylcarboxyamido)phenoxy] pentylthio -4 , 5-diphenylimidazole

henoxy]

-1-bromo-pentane, after purification on silica (eluent n-hexane/acetone 7:1). Yield 58%, m.p. 184-187°C.

EXAMPLE 10

2-r3-(imidazori.2-blpyrazol-l-yl)propylthio]-4,5-di- phenylimidazole

Z = imidazo[l,2-b]pyrazol-l-yl

Y ^****- ~(CH₂)₃- p = 0

To a suspension of imidazo [1,2-b]pyrazol (1.07 g, 10 mmol) in anhydrous dimethylformamide (8 ml) , sodium hydride is added (60% in oil, 400 mg, 10 mmol) and then stirred for 30 minutes at room temperature.

To the reaction mixture l-bromo-3-chloro propane (1 ml, 10 mmol) is added and stirred for 15 hours. Then 2,6-lutidine

(1.16 ml, 10 mmol) and 4,5-diphenylimidazole-2-thiol (2,74 g, 11 mmol) are added. After heating of 90°C for 18 h, the solvent is evaporated azeotroping with xylene. The crude oil obtained is purified on silica (eluent dichloromethane/methanol 100:1) .

650 mg of solid are obtained (1.66 mmol, yield 16%) . m.p. 170- 172°C.

EXAMPLE 11

2-r5- (imidazori.2-blpyrazol-1-yl)pentylthio1-4.5- diphenylimidazole

Z = imidazo[l, 2-b]pyrazol-l-yl

Y = -(CH₂)₅- p = 0

From l-(5-chloropentyl) -imidazo[l,2-b]pyrazole after purification on silica (eluent dichloromethane/methanol 100:1) , yield 35%, m.p. 45-48°C. EXAMPLE 12

2-(^"5-(2 , 3-diphenyl-imidazof1, 2-b]pyrazol-l-yl)pentylthio- 4 ,5-diphenylimidazole

Z = 2,3-diphenyl-imidazo[l,2-b]pyrazole Y = -(CH₂)₅- p = 0

From l-(5-chloropentyl) -2, 3-diphenyl-imidazo[1,2-b]pyrazole. Yield 67%, m.p. 54-57°C.

EXAMPLE 13 2-T3-fe-phenyl-imidazofl,2-blpyrazol-l-yl)propylthio1 -4 , 5-diphenylimidazole

Z = 6-phenylimidazopyrazole Y = -(CH₂)₃- p = 0 From l-(3-chloropropyl) -6-phenyl-imidazo[1, 2-b]pyrazole. Yield 45%, m.p. 164-165°C.

EXAMPLE 14

2 — r 3- f 2 , 4-dif luoro phenoxy) propylthio] -4 , 5-diphenylimidazole

F

-° λ^F Y = - (CH₂) ₃- p = 0

To a suspension of 4,5-diphenylimidazole-2-thiol (3 g, 11.9 mmol) in absolute ethanol (30 ml) in reflux, 2.6-lutidine (1.66 ml, 14.3 mmol) is added and then a solution of 3- (2, 4-difluoro phenoxy) -1-bromo-propane (3 g, 11.9 mmol) in absolute ethanol (10 ml) is added dropwise. The mixture is refluxed for 10 hours. Then filtered hot over dicalite and concentrated to dryness. The residue is taken up with ethyl acetate, then filtered and the organic layer is washed several times with water, dried over Na₂S0₄ and concentrated. The residue is chromatographed on silica (eluent dichloromethane) to give 3 g of product (7.1 mmol, yield 59%). m.p. 126-127°C.

EXAMPLE 15

2-15r- ( 2 .4-difluoro phenoxy) entylthio1-4 , 5-diphenylimidazole

From 5-(2,4-difluoro phenoxy) -1-bromo-pentane, yield 57%, m.p. 96-97°C.

EXAMPLE 16

2-r5-(4-fluoro phenoxy)pentylthio]-4 , 5-diphenylimidazole

From 5-(4-fluoro phenoxy) -1-bromo pentane, yield 54%, m.p. 92-94°C.

EXAMPLE 17

2-T5-fphenoxy)pentylthio]-4 , 5-diphenylimidazole

From 5-phenoxy-l-bromo pentane, yield 48%, m.p. 110-113°C. EXAMPLE 18

2-[3-(4-methylphenoxy)propylthiol-4 , 5-diphenylimidazole

Y = -(CH₂)₃-; p = 0; Z = -0- O

From 5-(4-methylphenoxy) -1-bromo propane, yield 27%, m.p. 133-134°C.

EXAMPLE 19

2-T3- ( 2 .5-dimethylphenoxy)propylthio]-4 , 5-diphenyl-imidazole

From 3-(2, 5-dimethylphenoxy) -1-bromo propane, yield 29%, m.p. 138-141°C.

EXAMPLE 20

2—r5—f2 , 5-dimethylphenoxy)pentylthio!-4.5-diphenyl-imidazole

From 5-(2, 5-dimethylphenoxy) -1-bromo pentane, yield 34%, m.p, 119-120°C.

EXAMPLE 21

2-[5-(2.3.5-trimethylphenoxy)pentylthiol-4 , 5-diphenyl- imidazole

From 5-(2, 3, 5-trimethylphenoxy) -1-bromo pentane, yield 62%, m.p. 136-138°C.

EXAMPLE 22 2- T 5- (4-methoxyphenoxy) pentylthio ] -4 , 5-diphenylimidazole

From 5-(4-methoxyphenoxy) -1-bromo pentane, yield 28%, m.p. 117-120°C.

EXAMPLE 23 2-T5-f3-methoxyphenoxy)pentylthio!-4.5-diphenylimidazole

From 5-(3-methoxyphenoxy) -1-bromo pentane, yield 41%, m.p. 105-107°C.

EXAMPLE 24 2-f5-f2-methoxyphenoxy)pentylthio!-4,5-diphenylimidazole

Y = -(CH₂)₅-; p = 0;

From 5-(2-methoxyphenoxy) -1-bromo pentane, yield 64%, m.p. 106-109°C.

EXAMPLE 25

2- Ϊ 5- (4-chlorophenoxy) entylthio] -4 , 5-diphenylimidazole

Y = -(CH₂)₅-; 0; Z == --°O- oV -C-l

From 5-(4-chlorophenoxy) -1-bromo pentane, yield 36%, m.p. 151-152°C.

EXAMPLE 26

2-T5-(3-trifluoromethylphenoxy)pentylthio!-4 , 5-diphenyl imidazole

From 5-(3-trifluoromethylphenoxy) -1-bromo pentane, yield 25%, oil.

EXAMPLE 27 2- T 5- ( 4-terbutγlphenoxy) pentylthio! -4 , 5-diphenylimidazole

Y = -(CH₂)₅-; p = 0;

- ^•^

From 5-(4-terbutylphenoxy) -1-bromo pentane, yield 39%, m.p. 132-134°C.

EXAMPLE 28 2-T5- (4-nitrophenoxy) entylthio1-4 , 5-diphenylimidazole

From 5-(4-nitrophenoxy) -1-bromo pentane, yield 62%, m.p. 131-132°C.

EXAMPLE 29 2—-f5—f Γ2-methoxy,4-methoxycarbonyl)phenoxy]pentylthio -4 , 5-diphenylimidazole

From 5-[ (2-methoxy, 4-methoxycarbonyl)phenoxy]-1-bromo pentane, yield 54%, m.p. 103-106°C.

EXAMPLE 30

2-r5- (2-pyridoxy) pentylthio]-4 , 5-diphenylimidazole

From 5-(2-pyridoxy) -1-bromo pentane, yield 76%, m.p. 118-120°C.

EXAMPLE 31

2-T5-(3 ,5-diterbutyl,4-hydroxy phenylthio)pentylthiol -4 , 5-diphenylimidazole

Y = -(CH₂)₅-; p = 0; ^'s^ }^~m From 5-(3,5-diterbutyl,4-hydroxy phenylthio) -1-bromo pentane, yield 29%, m.p. 45-50°C.

EXAMPLE 32

2-r5-f2-butylureido.3-dimethylaminophenoxy^propylthio] -4.5- diphenylimidazole

₂

From 2-butylureido, 3-dimethylaminophenol. Yield 70%, m.p. 156- 158°C.

EXAMPLE 33 2-f3-(2 ,4-difluorophenoxy) -2-hydroxy propylthio!-4 , 5-

p = 0 To a suspension of 4, 5-diphenylimidazole-2-thiol (7 g, 27.7 mmol) in absolute ethanol (100 ml) in reflux 2,6-lutidine (0.5 ml) is added, then a solution of 3 (2, 4-difluoro phenoxy)-1,2-epoxy propane (5.16 g, 27.7 mmol) in absolute ethanol (20 ml) is added dropwise. The mixture is refluxed for 3 hours then filtered hot over dicalite and concentrated to dryness. The residue is taken up with ethyl acetate, filtered and the organic layer is washed several times with water, dried over Na₂S0₄ and concentrated. The residue is chromatographed on silica (eluent dichloromethane) to give 8 g (18.2 mmol, yield 66%) of product, m.p. 56°C.

EXAMPLE 34

5-(4 ,5-diphenyl-imidazole-2-yl-thio) -thiazolidine-2 ,4-dione Y = single bond p = 0

To a solution of 4,5-diphenylimidazole-2-thiol (860 mg, 3.4 mmol) in absolute ethanol (10 ml) , DMF (7 ml) and 2,6-lutidine (0.6 ml), 5-bromo thiazolidine-2,4-dione (2 g, 5.1 mmol), dissolved in absolute ethanol (5 ml) is slowly added dropwise. The reaction mixture is stirred for 3 hours, ethanol is evaporated and the residual oil diluted with water and extracted with ethyl acetate. The organic layer is washed with water, dried over Na₂S0₄ and concentrated. The residue is taken up in diethyl ether/n-hexane 1:1 obtaining a yellow solid which is crystallized from diethyl ether/ethyl acetate. 0.47 g of the desired product are obtained (1.28 mmol, yield 38%) . m.p. 149-151°C.

Proceeding with the same working modality ( but at the reflux temperature of the solvent) the following derivative is prepared:

EXAMPLE 35

5-r3-(4 , 5-diphenyl-imidazole-2-yl-thio)propyl!- thiazolidine-2 ,4-dione.

Y = -(CH₂)₃- p = 0

Yield 20%, m.p. 170-172°C.

EXAMPLE 36 5—-C4—f2—f4.5-diphenyl-imidazol-2-yl-thio) ethoxy!benzyl -thiazolidine-2 , 4-dione

-(CH₂)₂-; p = 0

To a suspension of 4, 5-diphenylimidazole-2-thiol (2.14 g, 8.48 mmol) in absolute ethanol (25 ml) and 2,6-lutidine (1.18 ml, 10.2 mmol), heated to reflux temperature, a solution of 5-[4-(2-bromo-ethoxy) -benzyl]-thiazolidine-2,4-dione (2.87 g, 8.48 mmol) in absolute ethanol (50 ml) is slowly added dropwise in approximately 30 minutes. The mixture is refluxed for 30 hours then filtered hot over dicalite and concentrated to dryness. The residue is taken up with water and extracted with ethyl acetate. The organic layer is washed with water, with saturated solution of NaHC0₃, saturated solution of NaCl, dried over Na₂S0₄ and concentrated. The residue is chromatographed on silica (eluent: 1 dichloromethane; 2) dichloromethane acetate 9:1) to give 2.4 g (0.5 mmol, yield 14%) of product, m.p. 75-78°C.

Proceeding with the same working modality the following derivative is prepared:

EXAMPLE 37

5--T4—[2—(4 , 5-diphenyl-imidazole-2-yl-thio) -ethoxy) - benzylidene}-thiazolidine-2 , 4-dione

From 5-[4-(2-chloro-ethoxy)benzylidene]-thiazolidine- 2,4-dione, yield 26%, m.p. 83-85°C.

EXAMPLE 38

2-r5-(imidazor1,2-blpyrazol-l-yl)pentylsulfinyl] -4.5-diphenyl-imidazole

p = 1

Z = imidazo[l, 2-b]pyrazole

Y = -(CH₂)₅- To a solution of 2-[5-imidazo[1,2-b]pyrazol-l-yl) - pentylthio]-4, 5-diphenylimidazole (0.5 g, 1.17 mmol) in dichloromethane (10 ml) cooled to 0°C, a solution of m-chloro perbenzoic acid (0.24 g, 1.17 mmol) in dichloromethane (15 ml) is added dropwise. The cooling is stopped and the reaction mixture stirred for lh 30 . A 10% solution of sodium bisulfite is added and the layers separated. The aqueous layer is extracted with dichloromethane and the pooled organic layers are washed with a saturated solution of NaHC0₃, dried over Na₂S0₄ and concentrated to dryness. The residue is crystallized from diisopropyl ether, obtaining 300 mg (0.68 mmol, yield 58%) of product, m.p. 54-57°C.

EXAMPLE 39

3-(1.3-dioxolan-2-yl) -1.5-bis-(4 , 5-diphenylimidazol-2-yl- thio)pentane

To a mixture of 4 , 5-diphenylimidazole-2-thiol (2g, 7.92 mmol), 2,6-lutidine (0.55 ml, 4.75 mmol) in absolute ethanol (20 ml) , heated to reflux temperature, a solution of 3-(1, 3-dioxolan-2-yl) -pentyl-1, 5-bis-ptoluenesulfonate (1.86 g, 3.96 mmol) in absolute ethanol (10 ml) is added dropwise in approximately 30'. Then refluxed for 15 h and filtered over dicalite and the solvent evaporated. The residue is taken up with ethyl acetate, washed with a saturated solution of NaHC0₃, water and saturated solution of NaCl. The pooled organic layers are were dried over Na₂S0₄ and evaporated. The crude substance is chromatographed on silica (eluent n-hexane: ethyl acetate 7:3) to give the desired product (1.3 g, 2.06 mmol, yield 52%) . m.p. 190-192°C.

EXAMPLE 40

2—r5-f3.5-diterbutyl , 4-hydroxyphenylthio)pentylthio!- 4 , 5-diphenylimidazole hydrochloride To a solution of 2-[5-(3,5-diterbutyl,4-hydroxyphenylthio) pentylthio]-4,5-diphenylimidazole hydrochloride in 10 ml of methanol a methanolic solution of hydrogen chloride is added in stoichiometric amount at 0°C. The reaction mixture is allowed to waxen up to room temperature and evaporated in vacuo. The residue is dissolved in 15 ml of distilled water and lyophilized to give a quantitative amount of the title compound.

Formulation Example 1 With the usual methods of pharmaceutical technique, preparation can be made of capsules having the following composition:

2-oxyimino-l, 3-bis-(4 ,5-diphenyl imidazole-2-ylthio)propane 200 mg Starch 8 mg

Microcrystalline cellulose 23 mg

Talc 8 mg

Magnesium stearate 5 mg

Formulation Example 2

With the usual methods of pharmaceutical technique, preparation can be made of capsules having the following composition:

2-[5-(3 , 5-diterbutyl, 4-hydroxy phenylthio) pentylthio]-4 , 5-diphenylimidazole 200 mg

Starch 8 mg

Microcrystalline cellulose 23 mg

Talc 8 mg

Magnesium stearate 5 mg

Claims

A compound having the following formula (I)

wherein

Ph is phenyl; p is zero or 1;

X is a bond or a—(CH₂)_m—X—(CH₂)_n— group, wherein m and n being the same are 1 or 2 and X is a—(CH A)_t— group wherein A is hydrogen or hydroxy and t is zero or an integer of 1 to 10, or a group chosen from _/CO, C=NOR wherein R is hydrogen or an optionally omega-hydroxy substituted Cι-C₁₀ alkyl chain,

and in which q is 1 or 2;

Z is a group selected from 4, 5-diphenylimidazol-2- ylthio; an aryloxy group unsubstituted or monosubstituted by a substituent chosen independently from C,-C₆ alkyl, halo-C_]-C₆ alkyl, C,-C₆ alkoxy, halogen, amino and nitro; an aryloxy group substituted by two substituents chosen independently from C,-C₆ alkyl, halo-C,-C₆ alkyl, C,-C₆ alkoxy, halogen, amino, nitro,

alkoxy-carbonyl, di(C,-C₆ alkyl) amino and —NHCONH-Cj-C₆ alkyl; an aryloxy or arylthio group substituted by three substituents chosen independently from hydroxy and C,-C₆ alkyl;

2-pyridyloxy; an optionally substituted imidazo[l,2- b]pyrazol-l-yl group; 2,3-dihydro-lH-imidazo[l,2- b]pyrazol-l-yl; thiazolidyn-2,4-dione-5-yl;

A) when Z is 4, 5-diphenylimidazol-2-ylthio, then p a)

above, or b) m and n are 2 and X is

in which q is 1 or 2; or

B) when Z is an aryloxy group unsubstituted or substituted by a substituent chosen from C,-C₆ alkyl, halo— _!~C₆ alkyl, C,-C₆ alkoxy, halogen, amino or an aryloxy group substituted by two substituents chosen from C,-C₆ alkyl, halo-C]-C₆ alkyl, C,-C₆ alkoxy, halogen, amino, nitro, C,-C₆ alkoxy-carbonyl, di(C_]-C₆ alkyl)amino and —NHCONH-C^ alkyl, or an aryloxy or arylthio group substituted by three substituents chosen independently from hydroxy and C^Cg alkyl, or a group chosen from 2— yridyloxy, an optionally substituted imidazof1,2-b]pyrazol-l-yl group, 2,3—dihydro-lH-imidazo[1,2—-b]pyrazol-1-yl and

,

wherein R₂, R₃ and \ are as defined above, then p is zero or 1 and Y is a—(CH₂)_m—X—(CH₂)_n— group wherein m and n are 1, X is a—(CH A)— group wherein A and t are as defined above, or a group chosen from —CO—,

in which R is as defined above; or

C) when Z is thiazolidin—2,4— ione—5—yl, then p is zero and Y is a bond or a—(CH₂)_n—X—(CH₂)_n— group in which m and n are 1, X is a—(CH₂)_t— group in which t is as defined above.

A compound of formula (I), according to claim 1, wherein

Ph is phenyl; p is zero or 1;

Y is a bond or a—(CH₂)_n—X—(CH₂)_n— group, wherein each of and n is 1 or 2 and X is a group —(CHA)_t— wherein A is as defined in claim 1 and t is zero or an integer of 1 to 4, or a group

in which R is as defined in claim 1, _ NNHCON

Z is a group selected from

4,5-diphenylimidazol-2-ylthio; a phenoxy group unsubstituted or substituted by a substituent independently chosen from halogen, C_]-C₄ alkyl, C,-C₄ alkoxy, trifluoromethyl and nitro; a phenoxy group substituted by two substituents independently chosen from halogen, C,-C₄ alkyl, C,-C₄ alkoxy, trifluoromethyl, nitro, di(C,-C₄ alkyl)amino, C,-C₄ alkoxy-carbonyl and —NHCONH-^-C_j; alkyl; a phenoxy or phenylthio group substituted by three substituents independently chosen from hydroxy and C,-C₄ alkyl;

2-pyridyloxy; imidazofl,2-b]pyrazol-l-yl unsubstituted or substituted by one or two phenyl groups; thiazolidyn-2,4-dione-5-yl; and an

group wherein R, is as defined in claim 1;

and the pharmaceutically acceptable salts thereof.

3. A compound of formula (I), according to claim 1, wherein

Ph is phenyl; p is zero;

Z is 4, 5-diphenylimidazol-2-ylthio;

Y is a—(CH₂)_m—X—(CH₂)_n— group, wherein m and n are as defined in cla wherein R is hydrogen or C,-C₆ alkyl,

and the pharmaceutically acceptable salts thereof.

A compound of formula (I), according to claim 1, wherein Ph is phenyl; p is zero or 1; Z is a group selected from: a phenoxy group substituted by a substituent chosen from halogen, C,-C₄ alkyl, C,-C₄ alkoxy, trifluoromethyl and nitro; a phenoxy group substituted by two substituents independently chosen from halogen, C,-C₄ alkyl, C,-C₄ alkoxy, C,-C₄ alkoxy-carbonyl, di(Cι~C₄ alkyl) amino, and -*NHCONH-C,-C₆ alkyl; a phenoxy or phenyl-thio group substituted by three substituents independently chosen from hydroxy and C,-C₄ alkyl; R,

an imidazo[l, 2-b]

group wherein R, is

in which each of R₂, R₃ and R₄ is

R₄ independently hydrogen, C,-C₄ alkyl or C,-C₄ alkoxy; and Y is a—(CH₂)_m—X—(CH₂)_n— group wherein m and n are as defined in claim 1 and X is -(CHA)*— in which t is zero or an integer of 1 to 4 and A is as defined in claim 1; and the pharmaceutically acceptable salts thereof. 5. A compound of formula (I) , according to claim 1, wherein Ph is phenyl; p is zero; Z is thiazolidin—2,4—dione—5-yl; and

X is a bond or a—(CH₂)_m—X—(CH₂)_n— group wherein m and n are as defined in claim 1 and X is —(CH₂)_t— in which t is an integer of 1 to 4 and the pharmaceutically acceptable salts thereof.

6. A compound selected from:

2-oxyimino-l, 3-bis-(4, 5-diphenylimidazole-2-ylthio) - propane;

3-oxyimino-l,5-bis-(4, 5-diphenylimidazole-2-ylthio) - pentane; 2-hydrazonecarboxyamide-l, 3-bis-(4, 5-diphenylimidazole-

2-ylthio) -propane;

2-(O-pentyloxyimino) -1, 3-bis-(4,5-diphenylimidazole-2- ylthio) -propane;

2-0-(3-hydroxypropyl) -oxyimino-1, 3-bis-(4, 5-diphenyl- imidazole-2-yl-thio) -propane;

2-{3-[p-(2, 6-diisopropylphenylcarboxamido)phenoxy] propylthio}-4, 5-diphenylimidazole;

2-{5-[p-(2 , 6-diisopropylphenylcarboxyamido)phenoxy] pentylthio}-4, 5-diphenylimidazole; 2-{5-[p-(2,4, 6-trimethoxyphenylcarboxamido)phenoxy] pentylthio}-4 , 5-diphenylimidazole;

2-[3-(imidazo[1,2-b]pyrazol-l-yl)propylthio]-4,5- dipheny1imidazole;

2-[5-(imidazo[1,2-b]pyrazol-l-yl)pentylthio]-4, 5- diphenylimidazole;

2-[3-(6-phenyl-imidazo[l, 2-b]pyrazol-l-yl)propylthio]

-4,5-diphenylimidazole;

2-[3-(2,4-difluorophenoxy)propylthio]-4,5-diphenyl- imidazole; 2-[5-(2,4-difluorophenoxy)pentylthio]-4, 5-diphenyl- imidazole;

2-[5-(4-fluorophenoxy)pentylthio]-4,5-diphenyl- imidazole;

2-[3-(4-methylphenoxy)propylthio]-4,5-diphenyl- imidazole;

2-[3-(2,5-dimethylphenoxy)propylthio]-4, 5-diphenyl- imidazole;

2-[5-(2, 5-dimethylphenoxy)pentylthio]-4, 5-diphenyl- imidazole; 2-[5-(2, 3, 5-trimethylphenoxy)pentylthio]-4 , 5-diphenyl- imidazole;

2-[5-(4-methoxyphenoxy)pentylthio]-4 , 5-diphenyl- i idazole;

2-[5-(3-methoxyphenoxy)pentylthio]-4, 5-diphenyl- imidazole;

2-[5-(4-chlorophenoxy)pentylthio]-4 , 5-diphenyl- imidazole;

2-[5-(3-trifluoromethylphenoxy)pentylthio]-4 , 5- diphenylimidazole; 2-[5-(4-terbutylphenoxy)pentylthio]-4, 5-diphenyl- imidazole;

2-[5-(4-nitrophenoxy)pentylthio]-4, 5-diphenylimidazole;

2-{5-[ (2-methoxy, 4-methoxycarbonyl)phenoxy]pentylthio}-

4 ,5-diphenylimidazole; 2-[5-(2-pyridoxy)pentylthio]-4 , 5-diphenylimidazole;

2-[5-(3 , 5-diterbutyl, 4-hydroxy phenylthio)pentylthio]-

4, 5-diphenylimidazole;

2-[5-(2-butylureido, 3-dimethylaminophenoxy)propylthio]-

4, 5-diphenylimidazole; 2-[3-(2, 4-difluorophenoxy) -2-hydroxypropylthio]-4, 5- diphenylimidazole;

5-(4 , 5-diphenyl-imidazole-2-yl-thio) -thiazolidine-2,4- dione;

5-[3-(4 , 5-diphenylimidazole-2-ylthio)propyl]- thiazolidine-2 ,4-dione;

5-{4-[2-(4, 5-diphenylimidazole-2-ylthio) -ethoxy]benzyl} -thiazolidine-2,4-dione;

5-{4-[2-(4,5-diphenylimidazole-2-ylthio) -ethoxy) benzylidene}-thiazolidine-2,4-dione;

2-[5-(imidazo[1,2-b]pyrazol-1-yl)pentylsulfinyl]-4,5- diphenylimidazole; and

3-(l, 3-dioxolan-2-yl) -1,5-bis-(4, 5-diphenylimidazole-2- ylthio)pentane, if the case either as single isomers or as a mixture of isomers thereof, and the pharmaceutically acceptable forming salts thereof.

A process for the preparation of a compound of formula (I) or a salt thereof as claimed in claim 1, said process comprising:

a) reacting a 4 , 5-diphenylimidazole-2-thiol compound of formula (II)

in which Ph is phenyl, with a compound of formula (III)

Hal-(CH₂)_m-X-(CH₂)-Z (III) wherein Hal is halogen, m, n, X and Z are as defined in claim

1, thus obtaining a compound of the invention wherein p is zero; or

b) reacting a compound of formula (IV)

(O)_P-(CH₂)_m-CO-(CH₂) -Z (IV)

wherein

Ph, m, n, p and Z are as defined in claim 1, with a compound selected from the group (V) consisting of

H₂N-OR

H₂N-NHCONH₂ (V)

H₂N-NHCSNH₂ wherein R is as defined in claim 1, thus obtaining a compound of formula (I) wherein Y is a group

defined in claim 1; or

CH₂—CH—CHr-Z (VI)

O wherein m and Z are as defined in claim 1, thus obtaining a compound of the invention wherein p is zero and Y is a group —CHj—CH—CHj—; or

OH

_W_(CH₂)_m-X-(CH₂)_n-W (VII)

wherein

W is an activated derivative of an hydroxy group and m, n, and X are as defined in claim 1, thus obtaining a compound of the invention wherein Z is 4,5- diphenylimidazol-2-ylthio; or

e) oxidizing a compound of formula (VIII)

(VIII)

wherein

Ph, X and Z are as defined in claim 1, thus obtaining a compound of formula (I) wherein p is 1; and, if desired, converting a compound of formula (I) into another compound of formula (I) , and/or resolving a mixture of isomers of a compound of formula (I) into the single isomers, and/or converting a compound of formula (I) into a pharmaceutically acceptable salt thereof.

8. A pharmaceutical composition comprising a suitable carrier and/or diluent and, as an active principle, a compound of formula (I) as claimed in claim 1, or a pharmaceutically acceptable salt thereof.

9. A compound of formula (I), as defined in claim 1, or a pharmaceutically acceptable salt thereof, for use as ACAT inhibitor.

10. A compound of formula (I) , as defined in claim 1, or a pharmaceutically acceptable salt thereof, for use in the prevention of coronary heart disease, of cerebral ischemia; for use as antidyslipidaemic agent, antiatherosclerotic agent; for use in treating renal insufficiency and nephrotic syndromes.