CA2238812A1 - 2-(substituted sulfanyl)-3,5-dihydro-imidazol-4-one derivatives - Google Patents

Abstract

The compounds of formula (I): wherein R is phenyl or phenyl optionally substituted with one or more groups selected from halogen, alkyl, perfluoroalkyl, alkoxy, perfluoroalkoxy, hydroxy, alkanoyloxy, aroyloxy or arylalkanoyloxy; R3 is alkyl, aryl or arylalkyl; or a pharmaceutically acceptable salt thereof, are use for increasing HDL blood levels.

Description

CA 02238812 1998-0~-27 W o 97/19931 PCT~US96/19108 ? (SUBSTTTUTF.D ~U~,FANYL)-3.5-DTHYI)RO-TMIDA7,0-,~4-ON~.
nF,RTVATTVF.S

Rack~round of the lnven~ion s Numerous studies have ~lemonc~ated that both the risk of coronary heart disease (CHD) in hum~nc and the severity of e~cpçrim.ontsll atherosclerosis in :~nim~lc are inversely correlated with serum HDL cholesterol (HDL-C) concentrations (Russ et al, Am. J. Med.. 11 (1951) 480-493; Gofman et al, Circulation. 34 (1966) 679-697;
Millerand Miller, Lancet, I (1975) 16-19; Gordon et al, Circulation. 79 (1989) 8-15;
Stampfer et al, N. Engl. J. Med.. 325 (1991) 373-381; Badimon et al, Lab. Invest.. 60 (1989) 455-461). Atherosclerosis is the process of accumulation of cholesterol within the arterial wall which results in the occlusion, or stenosis, of coronary and cerebral arterial vessels and subsequent myocardial infarction and stroke. Angiographical15 studies have shown that elevated level of some HDL particles in hum~nc appears to be correlated to a decreased number of sites of stenosis in the coronary arteries of humans (Milleretal,Br. Med.J.. 282(1981) 1741-1744).

There are several mech~nicmc by which HDL may protect against the 20 progression of atherosclerosis. Studies in vitro have shown that HDL is capable of removing cholesterol from cells (Picardo et al, Arteriosclerosis. ~ (1986) 434-441).
Data of this nature suggest that one antiatherogenic property of HDL may lie in its ability to deplete tissues of excess free cholesterol and eventually lead to the delivery of this cholesterol to the liver (Glomset, J. Lipid Res.. 2 (1968) 155-167). This has been 25 supported by experiments showing efficient transfer of cholesterol from HDL to the liver (Glass et al, Circulation. 66 (Suppl. I) (1982) 102; MacKinnon et al, J. Biol.
Chem., 261 (1986) 2548-2552). In addition, HDL may serve as a reservoir in the circulation for apoproteins necessary for the rapid metabolism of triglyceride-rich li~uproLeins (Grow and Fried, J. Biol. Chem.. 253 (1978) 1834-1841; Lagocki and Scanu, J. Biol. Chem.. 255 (1980) 3701-3706; Schaefer et al, J. Lipid Res.~ 23 (1982) 1259-1273). Accordingly, agents which increase HDL cholesterol concentrations are useful as anti-atherosclerotic agents, particularly in the treatment of dyslipoproteinemias and coronary heart disease.

US 5,411,981 discloses N-phenyl imidazolidines of the following formula W O 97/19931 PCT~US96/19108 (A-I) as anti-androgenic agents useful in the lln~ t of cancers of the breast, brain, ovaries, bladder, liver and kidney:

R1 ~N~A~l3 (A-l) s in which -A-B- is J~ R3 ~

(a) (b) where Rl is cyano, nitro or halogen; R2 is trifluoromethyl or halogen; X is 10 oxygen or sulfur; Y is oxygen, sulfur or nitrogen and R3 is hydrogen or a vast variety of organic groups.

Related publication EP 578516 emphasizes compounds of formula (A-Ia), with special emphasis on the 4-cyano-2-trifluoromethyl-phenyl group in each of the 15 disclosed species.

WO 94/20460 discloses a genus of compounds of formula (A-II) as angiotensin-II receptor antagonists, useful for the treatment of hypertension, congestive heart failure, renal failure and glaucoma.
(CH2)n-HET

where HETis R2~

(A-l 1) (A-l 11) CA 02238812 1998-0~-27 W O 97/19931 PCT~US96/19108 In the generic disclosure, HET represents numerous heterocycles, one of which is an imi~l~701i~1inone (A-III) in which R2 may be an 2-8 C alkylthio group among other things. There is no specific example of a compound disclosed in the ~iocllm~ont that corresponds with those variables . R22 is a 3-4 m~mhered polymethylene (spiro) group.

T)escriDtion of Tnvention In accordance with this invention there is provided a ~roup of 2-(substituted sulfanyl) dihydro-imid~7010nes of formula I, R.N~N
SR3 (I) wherein lS R is phenyl or phenyl optionally substituted with one or more groups the same or different selected from halogen, aL~<yl of 1 to 6 carbon atoms, perfluoroalkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, perfluoroalkoxy of 1 to 6 carbon atoms, hydroxy, alkanoyloxy of 2 to 6 carbon atoms, aroyloxy of 7 to 11 carbon atoms or arylalkanoyloxy of 8 to 16 carbon atoms;
R3 is alkyl of 1 to 6 carbon atoms, aryl of 6 to 10 car'oon atoms or arylalkyl of 7 to 12 carbon atoms;
or a pharmaceutically acceptable salt thereof.

The pharmaceutically acceptable salts are those derived from such organic and inorganic acids as: acetic, lactic, citric, tartaric, succinic, maleic, malonic,hydrochloric, hydrobromic, phosphoric, nitric, sulfuric, methanesulfonic, and similarly known acceptable acids. The terms alkyl and alkoxy as used as a group or part of a group, e.g perfluoro-alkyl or -alkoxy means a straight chain or branched chain, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, neopentyl, hexyl, methoxy, ethoxy, propoxy, butoxy, isobutoxy, hexyloxy, and the like.

CA 02238812 1998-0~-27 W O 97/19931 PCT~US96/19108 FY~mples of halogen are fluorine, chlorine, I~ ine and iodine. Examples of aryl as a group or part of a group such as arylalkyl or aroyl are phenyl and naphthyl.
FY~mr1es of alkanoyloxy as a group or part of a group are acetoxy, propanoyloxy or butanoyloxy.
s A preferred group of compounds are those of formula I:

R N~N
SR3 (I) wll~,l~ill R is phenyl or phenyl optionally substituted with one or more groups the same or different selected from halogen, alkyl of 1 to 3 carbon atoms, perfluoromethyl, aL~coxy of l to 3 carbon atoms, perfluoromethoxy, hydroxy or alkanoyloxy of 2 to 4 carbon atoms;
R3 is alkyl of l to 3 carbon atoms or arylalkyl or 7 to 9 carbon atoms;
or a pharmaceutically acceptable salt thereof.

The most ~l~Ç~ d compounds of this invention are:

2-Ethylsulfanyl-3-(4-fluorophenyl)-3,5-dihydro-imidazol-4-one or a ph~rm~ceutically acceptable salt thereof;

3-(5-Chloro-2-methylphenyl)-2-ethylsulfanyl-3,5-dihydro-imifl~ 1-4-one or a ph~rm~reutically acceptable salt thereof;
3-(S-Chloro-2-methoxyphenyl)-2-ethylsulfanyl-3~5-dihydro-imi~1~7c-1-4-one or a ph~rm~eutic~lly acceptable salt thereof;

3-(2,6-Dichlorophenyl)-2-ethylsulfanyl-3,5-dihydlo-imidazol-4-one or a ph~rm~eutically acceptable salt thereof;

CA 02238812 1998-0~-27 2-Benzylsulfanyl-3-(5-chloro-2-methylphenyl)-3,5-dihydro-imid~701-4-one or a ph~rm~ euti~ ~lly acceptable salt thereof;

3-(2-Chlorophenyl)-2-ethylsulfanyl-3,5-dihydro-imi~ 701-4-one or a 5 ph~rm~e~ltic~lly acceptable salt thereof;

2-Ethylsulfanyl-3-(2-tolyl)-3,5-dihydro-imicl~701-4-one or a pharmaceutically acceptable salt thereof;

3-(2-Chloro-6-methylphenyl)-2-ethylsulfanyl-3,5-dihydro-imifl~7ol-4-one or a ph~rm~r.elltically acceptable salt thereof;

2-Ethylsulfanyl-3-phenyl-3,5-dihydro-imidazol-4-one or a pharmaceutically acceptable salt thereof;
3-(2,6-Dimethylphenyl)-2-ethylsulfanyl-3,5-dihydro-imidazol-4-one or a pharmaceutically acceptable salt thereof;

This invention also provides processes for preparh1g the compounds of formula 20 I or pharmaceutically acceptable salts thereof which processes comprise:

a) reacting a 2-thioxo-imidazolidin-4-one of formula (A):
o9_~

R ~
S

(A) wherein R is as defined above with methyl iodide to give a corresponding compound of formula I wherein R3 is methyl, or b) reacting a thiourea amide of formula 3:

W O 97/19931 PCT~US96/19108 H H
R~ N~r N , CONH2 S
(3) wherein R is as defined above, with a compound of formula:

where R3 is as defined above and X is a halogen to give a compound of formula I
wherein R and R5 are as defined above, and if desired isolating the compound of formula I as the free base or converting to a pharrn:~eu~ical salt thereof.
With regard to process a) the compounds of this invention where R3 is methyl (B) can be prepared by alkylation of 2-thioxo-imidazolidin-4-ones (A) with methyl iodide. The reaction proceeds in poor yield. The product is difficult to purify as a pharmaceutically acceptable salt. The alkylation has not been successfully carried out 15 with aL~cyl iodides larger than methyl.

~ Mel ~
R~ N~NH ~ N~N . HI
S SMe (A) (B) With regard to process b) the compounds of the present invention are ~-c~
according to the ~Ic;Çe~l~d general sequence of reactions outlined in the scheme below:

CA 02238812 1998-0~-27 .

H2NCH2cONH2-Hcl McOH ~ H2NCH2cONH2 s (1) (2) R--NCS /R- NCS
Ba~,e H H o~
R,N~N ~CONH2 R3-X,ELoH R.N~N

(3) (4) S R

In a preferred sequence an amino acid amide hydrochloride (1) is converted to the base (2) with sodium methoxide in methanol. An appropriate isothiocyanate is5 added at room temperature to the amino acid amide in chloroform or methylene chloride. The mixture is heated to reflux, then heathlg is discontinued and stirring is cnntinue~l for 20 min~ltes to 3 hours. The thiourea-amide (3) is isolated by standard procedures. In an alternative procedure, (3) can be obtained from the amino acid amide hydrochloride ( 1 ) . In this procedure, ( I ) is r~acted with an isothiocyanate in the 10 presence of a base such as triethylamine. The thiourea-amide (3) is reacted with two equivalents of alkyl halide (or aryl halide) in ethanol at reflux for 2 to 5 hours. The ~mmc.ni~ that forms during cyclization effectively scavenges the hydrohalide formed during alkylation, allowing the title compounds (4) to be isolated as the free base.
Desired salts can be prepared by standard methods.
This invention also provides a pharmaceutical composition comprising a compound of formula I or a pharmaceutical salt thereof either alone or in combin~tion with excipients (i.e. phalmaceutically acceptable carrier or m:~terisllc with nopharmacological effects). Such compositions are useful in the lle~ le~lt of 20 atherosclerotic conditions such as dyslipoproteinemias and coronary heart disease, in that they increase the blood serum high density lipoprotein concentration of ",;..,.",~lc treated with the compounds.

The precise dosage to be employed depends upon several factors including the 25 host, whether in veterinary medicine or human medicine, the nature and severity of the CA 02238812 1998-0~-27 W O 97/19931 PCTnUS96/19108 conrlition being treated, the mode of ~Aminictration and the particular active sll~st~nre employed. The compounds may be ~Aministtored by any convçntion~l route, in partieular enterally, preferably orally in the form of tablets or eapsules. ~Amini~t~red compounds can be in the free form or pharm~ceutiç~lly acceptable salt form as 5 a~lu~liate~ for use as a pharmaceutical, particularly for use in the prophylaetie or eurative tre~tm~ont of atherosclerosis and sequelae (angina pectoris, myocardialinfarction, arrhythmias, heart failure, kidney failure stroke, peripheral arterial oeelusion, and related disease states). These measures will slow the rate of progress of the disease state and assist the body in reversing the process direction in a natural 10 manner.

Any suitable carrier known to the art can be used to prepare the pharm~f~elltir~l eompositions. In such a composition, the carrier may be a solid, liquid or mi~Lule of a solid and a liquid. Solid compositions include powders, tablets and capsules. A solid 15 carrier can be one or more substances which may also act as a flavoring agent, lubricant, solubilizer, suspending agent, binder, or tablet disintegrant. In powders, the earrier is a finely divided solid which is in admixture with the finely divided active ingredient. In tablets the active ingredient is mixed with a carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.
20 Suitable solid carriers are m~gne,ci um carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methyl cellulose, hydroxymethyl cellulose, sodium carboxymethyl cellulose, a low melting wax, coeoa butter, and the like. Encapsulating materials may also be employed with the compounds of this invention, and the term "composition" is intended to include the active ingredient in 25 comhin~tion with an encapsulating material as a formulation, with or without other carriers. Cachets may also be used in the delivery of the anti-atherosclerotic m~Ai~ment of this invention.

Sterile liquid compositions include solutions, suspensions, emulsions, syrups 30 and elixirs. The compounds of this invention may be dissolved or suspended in the ph~ e~ lly acceptable carrier, such as sterile water, sterile organic solvent or a Lulc of both. Preferably the liquid carrier is one suitable for parental injection.
Where the compounds are sufficiently soluble they can be dissolved directly in norm 1 saline with or without the use of suitable organic solvents, such as propylene glyeol or 35 polyethylene glycol. If desired, dispersions of the ~Inely divided compounds can be CA 02238812 1998-0~-27 made-up in aqueous starch or sodium carboxymethyl cellulose solution, or in a s~lit~l~'o oil, such as arachis oil. Liquid pharmaceutical compositions which are sterile sol~1tion~
or suspensions can be utilized by intramuscular, intraperitoneal or suh~ n l~so~ls injection. In many in~t~n~eS a liquid composition form may be used instead of the ~erel~Gd solid oral method of ~rimini~tration.

It is ~J~cr~l~ed to prepare unit dosage forms of the compounds for standard ~-lminictration regimens. In this way, the composition can be subdivided readily into smaller doses at the physicians direction. For example, unit dosages may be made up in packeted powders, vials or ampoules and preferably in capsule or tablet form. The active compound present in these unit dosage fomls of the composition may be present in an amount of from about one gram to about fifteen grams or more, for single or multiple daily ,l~imini~tration, according to the par~icular need of the patient. The daily dose of active compound will vary depending UpOII the route of ~dministration~ the size, age and sex of the patient, the severity of ~he disease state, and the response to the therapy as traced by blood ,malysis and the patients recovery rate. By initiating the ~I~,a~ t regimen with a minimal daily dose of about one gram, the blood levels of HDL and the patients s~ -pto---atic relief analysis may be used to determine whether a larger dose is indicated. Based upon the data presented below, the projected daily dose for both human and veterinary use will be fiom about 10 to about 200 milligrams/kilogram per day. However, in general, satisfactory results are inflir~,~te~ to be obtained at daily dosages in the range of from 400 milligrams to about 2000 milligrams, conveniently adrninistered in divided doses two to four times a day.
The ability of the compounds of this invention to increase blood serum HDL
levels was established by the following standard experimental procedure for determin~3tion of HDL cholesterol:

Male Sprague-Dawley rats weighing 200-225 g are housed two per cage and fed Purina Rodent Chow Special Mix 5001-S supplemented with 0.25 % cholic acid and 1.0 % cholesterol and water ad libitum for 8 days. Each test substance is ~lminict~ored to a group of six rats fed the same diet with the test diet mixed in as 0.005 - 0.1 % of the total diet. Body weight and foocl consumption are recorded prior to diet ~q~lmini~tration and at termination. Typical doses of the test substances are 5 - 100 mg/kg/day.

CA 02238812 1998-0~-27 W O 97/19931 PCT~US96/19108 At termination, blood is collected from ~nesthçti7ecl rats and the serum is s~ ;d by centrifugation. Total serum cholesterol is assayed using the Sigma Di~gn- sti~s enzymatic kit for the determination of cholesterol, Sigma Procedure No.
5 352, mo lif;e~l for use with ninety-six well microtiter plates. After recon~;tl~tion with water the reagent cont~in~ 300 U/l cholesterol oxidase, 100 U/l cholesterol esterase, 1000 U/l horse radish peroxidase, 0.3 mmnlçs/l 4-aminoantipyrine and 30.0 mmol~
p-hydroxybenzenesulfonate in a pH 6.5 buffer. In the reaction cholesterol is oxidized to produce hydrogen peroxide which is used to form a quinoneimine dye. The 10 concentration of dye formed is measured spectrophotometrically by absorbance at 490 nrn after incubation at 25 ~C for 30 minutes. The concentration of cholesterol was clel.. in~d for each serum sample relative to a commercial standard from Sigma.

HDL cholesterol concentrations in serum are determined by separation of 15 lipoprotein classes by fast protein liquid chromatography (FPLC~ by a modification of the method of Kieft et al., J. Lipid Res, 32 (1991) 859-866. 25 ul of serum is injected onto Superose 12 and Superose 6 (Pharmacia), in series, with a column buffer of 0.05 M Tris (2-amino-2-hydroxymethyl-1,3-propanediol) and 0.15 M sodium chloride at aflow rate of 0.5 mVmin. The eluted sample is mixed on line with Boehringer-~nnh.oim 20 cholesterol reagent pumped at 0.2 ml/min. The combined eluents are mixed and incubated on line through a knitted coil (Applied Biosciences) m~in~ined at a temperature of 45C. The eluent is monitored by me,tsurillg absorbance at 490 nm and gives a continuous absorbance signal proportional to the cholesterol concentration. The relative concentration of each lipoprotein class is calcul;lted as the per cent of total 25 absorbance. HDL cholesterol concentration, in serum, is calculated as the per cent of total cholesterol as deterrnined by FPLC multiplied by the total serum cholesterol concentration.

The compounds of the present invention increase HDL cholesterol 30 concentrations as summarized in Table I:

W O 97/19931 PCT~US96/19108 Table I
Compound Dose Dur~tion of HDL Cholesterol of (mglkg/day) Tre~tment (days3 Level Increase (%) Example 2-Ethvlsulfanvl-~-(4-fllloronllenvl)-3~5-dihvdro-imida7.ol-4-one Glycin:lmide. (5.0 g) and 4-fluorophenyl-isothiocyanate (9.18 g) were stirred inchloroform (200 mL). The mixture was heated at reflux for 5 minutes then stirred at 10 ~m'~)ient temperature for 20 minutes. The precipitated solid was collected by filtration, washed with chloroform and air dried to give 2-L3-(4-fluorophenyl)-thioureido]-açet~micle (10.7 g) as a light pink solid, m.p. 168-170 C (dec.). Mass spectrum (EI, M.+) m/z 277. lH-NMR (DMSO-d6; 400 MHz) ~ 9.97 (broad s, lH), 7.82 (broad s, lH), 7.45-7.52 (m, 3H), 7.10-7.17 (m, 3H), and 4.06 ppm (s, 2H).

A mixture of 2-[3-(4-fluorophenyl)-thioureido]-acetamide (9.1 g) and ethyl iodide (12.5 g) was heated at re~flux in ethanol (200 mL) for 4 hours. The solvent was evaporated. The residue was dissolved in ethyl acetate (500 rnL) then washed with water. The organic phase was extracted with 2N HCl (2 X 400 mL). The acid extract 5 was made basic with 5% sodium bicarbonate solution. The precipitate was c~ t~l by filtration and dried. Crys~lli7:~tion from diethyl ether afforded the title compound (2.85 g) as an off-white solid, m.p. 114-115 C. Anal. Calcd. for. Cl1 Hll F N2 O S: C,55.45; H, 4.65; N, 11.76. Found: C, 55.17; H, 4.54; N,11.81. Mass spectrum (EI, M.+) m/z 238. 1H-NMR (DMSO-d6; 4()0 MHz) o 7.32-7.39 (m, 4H), 4.30 (s, 2H), 3.07 (q, 2H), and 1.28 ppm (t, 3H).

3-(5-Chloro-2-methvlphenvl)-~-etllvlslllf~nvl-3~5-dillvdro-imi(l~,ol--1-one Glycinamide (10.08 g) and 5-chloro-2-metllylphen~l-isothiocyanate (23 g) were heated at reflux in chloroforrn (300 mL) for 30 minutes. The mixture was then stirred at ambient temperature for 3 hours. The precipitated solid was collected by filtration, 20 washed with chloroform and air dried to give 2-[3-(5-chloro-2-methylphenyl)-thioureido]-acetamide (28.5 g), m.p. 162- 164 C. Mass spectrum (EI, M.+) m/z 257/259. IH-NMR (DMSO-d6; 40() MHz) o 9.46 (s, lH), 7.83 (s, lH), 7.51 (d, 2H), 7.24 (d, lH), 7.24 (d, lH), 7.18 (d, lH), 7.15 (m, 2H), 4.06 (d, 2H), and 2.16 ppm (s, 3H).
A rnixture of 2-[3-(5-chloro-2-methylphenyl)-thioureido]-acetamide (25.8g) and ethyl iodide (32.0 g) was heated at reflux in ethanol (500 mL) for S hours. The solvent was evaporated. The residue was dissolved in ethyl acet;lte (500 n3L) and water (300 mL). The organic phase was washed Witll water, dried over anhydrous MgSO4, then 30 evaporated to dryness. The residue was triturated with diethyl ether and the solid was collected by filtration and dried to give the title compound (17.0 g) as a yellow solid, m.p. 137-139 C. Ar~al. Calcd. for. C12 H13 Cl N2 O S: C, 53.63; H, 4.88; N,10.42.
Found: C, 53.58; H, 4.74; N, 10.32. Mass spectmn1 (EI, M.~) m/z 268/270. 1H-NMR (DMSO-d6; 400 MHz) o 7.45-7.49 (m, IH), 7.40-7.43 (m, ~H), 4.35 ~dd, 2H), 3.07 (m, 2H), 2.1 (s, 3H), and 1.~8 ppm (t~ 3H).

CA 02238812 1998-0~-27 W O 97/19931 PCT~US96/19108 F.XAMPLE 3 -3-(5-Chloro-2-methoxyDhenvl)-2-ethvlslllfanvl-3.5-5dih v~l ro-i~nida~.ol-4-one A mixture of glycin~mi~ hydrochloride (5.5 g), triethyl amine (5.05 g), 5-chloro-2-methoxyphenyl-isothiocyanate (9.95 g), and chloroform (500 rnL) were heated at reflux for 3 hours. The mixture was then cooled to arnbient temperature and 10 washed with water (300 mL). The organic phase was separated. Precipitate formed upon standing. The solid was collected by filtratiol1, washed with water, then with diethyl ether and air dried to give 2-[3-(5-c~hloro-2-methoxyphenyl)-thioureido]-acet~micle (12.8 g), m.p. 166-169 C (dec.). This compound was used without further purification for the preparation of the title compound.
A mixture of 2-[3-(5-chloro-2-methoxyphenyl)-thioureido]-acet~mide (11.0 g) and ethyl iodide (12.5 g) in ethanol (400 mL) was heated at reflux for 4.5 hours. The solvent was evaporated. The residue was dissolved in chloroforrn (500 rnL) and washed with water. The organic phase w.lS dried over anhydrous MgSO4, then 20 evaporated to dryness. The residue was crystallized from ethanol to give the title compound (6.1 g) as a tan solid, m.p. 113-115 C. Anal. Calcd. for. C12 H13 Cl N2~2 S: C, 50.61; H, 4.60; N,9.84. Found: C, 50.32; H, 4.59; N, 9.77. Mass spectrum (ESI+, [M+H]+) m/z 285/287. lH-NMR (DMSO-d6; 400 MHz) o 7.53 (m, lH), 7.41 (d, lH), 7.22 (d, lH), 4.31 (dd, 2H), 3.77 (s, 3H), 3.05 (m, 2H), and 1.26 ppm 25 (t, 3H).

~XAMPLE 4 3-(2.6-DichloroDhenvl)-2-ethvl~lllfanvl-3~-dihvdro-;mida~ol-4-one 2-[3-(2,6-Dichlorophenyl)-thioureido]-acetamide was prepared by the procedure described in Example '7 USillg 10.8 g of 2,6-dichlorophenyl-isothiocyanate and 29.6 g of glycinamide. The product was obtained (54 g) as a solid, m.p. 189-191~
C. Mass spectrum (+FAB, [M+Hl+) mlz 278/280/287. This intermediate was used in 35 the next paragraph without further purification.

W O 97/19931 PCTnJS96/19108 The title compound was ~lepal~d by the procedure described in Example 2 using 27.8 g of 2-[3-(2,6-dichlorophenyl)-thioureido]-acetqmide and 31.2 g of ethyl iodide. 12.8 g of the title compound was obt~ined, m.p. 122-124 C. Anal. Calcd. for.
C11 H1o Cl2 N2 O S: C, 45.69; H, 3.49; N, 9.69. Found: C, 45.62; H, 3.33; N, 9.43. Mass spectrum (+FAB, [M+H]+) m/z 289/291/293. lH-NMR (DMSO-d6; 400 MHz) ~ 7.72 (s, lH), 7.70 (s, lH), 7.58 (t, lH), 4.50 (s, 2H), 3.10 (q, 2H), and1.27 ppm (t, 3H).

F'~AMPLE ~

2-Ben~ylsulfanvl-3-~5-chloro-2-methvlnhenvl)-3.5-dihvdro-imida~ 4-one lS A mixture of 2-[3-(5-chloro-2-methylphenyl)-thioureido]-:~~et~n~ifle (20.6g), benzyl chloride (25.0 g), and eth~nol (350 mL) was heated at reflux for 2.5 hours. The insolubles were removed by filtration and discarded. The filtrate was concentrated to one-half volume. Diethyl ether (300 mL) was added. The precipitated solid was separated by filtration and disc~rded. The filtra~e was evaporated to dryness. The 20 residue was dissolved in chlorofoml (30() mL) and washed with water. The organic phase was dried over anhydrous MgSO4, decololized on carbon then evaporated to dryness. The residue was triturated with diethyl ether ~o give the title compound (14.2 g) as an off-white solid, m.p. 140-142 C. Anal. Calcd. for. C17 H1s Cl N2 0 S: C, 61.72; H, 4.57; N, 8.47. Found: C, 61.6; H, 4.39; N, 8.37. Mass spectrum (EI, M.+) m/z 330/332. 1H-NMR (DMSO-d6; 400 MHz) o 7.46 (m, lH), 7.42 (m, 2H), 7.38 (d, 2H), 7.22-7.3'7 (m, 3H), 4.31-4.48 (m, 4H), and 2.06 ppm (s, 3H).

~XAMPLE 6 3-(2-ChloroDhenyl)-2-ethvlslllfanvl-3~5-dillvdro-imida~ol-4-one 2-[3-(7-Chlorophenyl)-thioureido]-;lcet:3mide was prepared by the procedure described in Example 3 USillg 16.95 g of ~-chlorophenyl-isothiocyanate and equivalent amounts of all other reactants. 18.8 Grams of the desired product was obtained, m.p.
161-163~ C. Anal. Calcd. for. Cg Hlo Cl N3 O S: C, 44.35; H, 4.414; N, 17.24.

CA 02238812 1998-0=.-27 W O 97/19931 PCT~US96/19108 Found: C, 43.99; H, 3.91; N, 17.12. Mass spectrum (+FAB, [M+H]+) m/z 244/246.
lH-NMR (DMSO-d6; 400 MHz) o 9.57 (s, lH), 8.06 (t, lH), 7.71 (d, lH), 7.52 (s, - lH), 7.47 (m, lH), 7.28-7.32 (m, lH), 7.18-7.22 (m, 2H), and 4.09 ppm (d, 2H).

A mixture of 2-[3-(2-chlorophenyl)-thioureido]-acetamide (12.2 g), ethyl iodide (15.6 g), and etharlol (200 mL) was heated at reflux for 5 hours. The solvent was eva~laled. The residue was dissolved in ethyl acetate (400 rnL) and water (300 mL).
The organic phase was washed with water (2x300 mL). The organic phase was dhen extracted with 2N HCI (2x500 mL). The acid extract was neutralized with solid sodium bicarbonate and extracted with ethyl acetate. The organic phase was washed with water, dried over anhydrous MgSO4 then evaporated to dryness. The residue was dissolved in ethanol and the solution was satul ated with hydrogen chloride. The solvent was evaporated and the residue was crystallized fi-om ethyl acetate to give the hydrochloride salt of dhe title compound (8.4 g) as an off-white solid, m.p. 149-150~ C (dec.). Anal.
Calcd. for. Cl 1 Hl l Cl N2 O S . HCI: C, 45.37; H, 4.15; N, 9.62. Found: C, 44.97;
H, 4.06; N, 9.51. Mass spectrum (EI, M.+) m/z 254/256. IH-NMR (DMSO-d6; 400 MHz) ~; 7.69 (m, lH), 7.50-7.58 (m, 3H), 4.45 (q, 2H), 3.11-3.17 (m, 2H), and 1.27 ppm (t, 3H).

2-Ethylsulfanyl-3-(2-tolyl)-3~5-dillydro-imida~,ol-4-one 2-[3-(2-Tolyl)-thioureido]-acetamide was prepared by the procedure described 25 in the first paragraph of Example 3 using 14.9 g of ~-tolyl-isothiocyanate and equivalent amounts of all other reacun~s. 17.1 Grams of product was obt~ined, m.p.
169-171 C (dec.). This compound was used without further purification in dhe next paragraph.

- 30 The tide compound was prepared by the procedure described in Example 6 using 11.2 g of 2-r3-(2-tolyl)-thioureido]-acetamide and 15.6 g of edhyl iodide.~ Cry~t~11i7:~tion from ethyl acetate afforded the hydrochloride salt of the title compound as a white solid (6.8 g), m.p. 156-158 C (dec.). Anal. Calcd. for. C12 H14 N2 0 S .
HCl: C, 53.23; H, 5.58; N, 10.34. Found: C, 52.96; H, 5.49; N, 10.25. Mass W O 97/19931 PCT~US96/19108 spectrum (EI, M.+) m/z 234. lH-NMR (DMSO-d6; 400 MHz) ~8.75 (broad s, 2H), 7.43 (m, 2H), 7.35 (m, lH), 7.30 (m, lH), 4.53 (q, 2H), 3.18-3.20 (m, 2H), and 1.29 ppm (t, 3H).

l~XAMPLE X

3-(2-Chloro-6-methvlol1envl)-2-ethvlsulf~nvl-3~5-dihvdro-imicl.l~.ol- 1-one 2-[3-(2-Chloro-6-methylphenyl)-thioureido]-acetamide was prepared by the procedure described in Example 2 using 18.3 g of 2-chloro-6-methylphenyl-isothiocyanate and 12.0 g of glycin;mlide. 22.8 Grams of the product was obtained, m.p. 161-163~ C (dec.). This compound was used without further purification in the next paragraph.
The title compound was prepared by the procedure described in Exarnple 6 using 12.9 g of 2-[3-(2-chloro-6-methylpllenyl)-rhioureido]-acetamide, and 18.0 g of ethyl iodide. The hydrochloride salt was prepared in ethereal hydrogen chloride.Crystallization from ethyl acetate afforded the title compound as the mono-hydrochloride as a light yellow solid (4.9 g), m p. 157-154~ C (dec.). Anal. Calcd.
for. C12 H13 Cl N2 0 S . HCI: C, 47.'~7; H, 4.62; N, 9.18. Found: C, 46.99; H, 4.60; N, 9.16. Mass spectrum (+FAB, IM+H~+) m/z 269/271. lH-NMR (DMSO-d6;
400 MHz) ~ 8.28 (broad s, 2H), 7.51 (m, lH), 7.44 (t, lH), 7.39 (m, lH), 4.51 (q, 2H), 3.12 (q, 2H), 2.17 (s, 3H), and 1.27 ppm (t, 3H).

2-F.thvl.slllfanvl-3-pllenvl-3~5-dihvdro-imi(la~ol-4-one A mixture of glycinamide hydrochloride (8.25 g), triethyl amine (10.0 g), phenyl-isothiocyanate (10.1 g), and methylene chloride (300 mL) was heated at reflux for 1 hour. The mixture was stirred at ambient temperature for 2 hours. The precipitate was collected by filtration, washed with methylene chloride, then with diethyl ether and air dried to give 2-(3-phenyl-thioureido)-acetamide (9.7 g), m.p. 150-152 C. Anal.

CA 02238812 1998-0~-27 W O 97/19931 PCT~US96/19108 - Calcd. for. Cg H11 N3 O S: C, 51.66; H, 5.30; N, 20.08. Found: C, 51.41; H, 5.04;
N, 20.02. Mass spectrum (EI, M.+) mtz 209. lH-NMR (DMSO-d6; 400 MHz) ~ 9.88 - (s, lH), 7.70 (t, lH), 7.52 (s, lH), 7.47 (d, 2H), 7.31 (t, 2H), 7.15 (s, lH), 7.09 (t, lH), and 4.08 ppm (d, 2H).

A mixLu~G of 2-(3-phenyl-thioureido)-acetamide (7.1 g), ethyl iodide (18.0 g), and ethanol (300 nL) was heated at reflux for 2 hours. The solvent was evaporated.
The residue was dissolved in chloroform (300 mL) and water (300 mL). The organicphase was washed with water, dried over anhydrous MgSO4, then evaporated to 10 dryness. The residue was crystallized from ethyl acetate/hexane to give the title compound (3.1 g), m.p. 79-81 C. Anal. Calcd. for. Cl l H12 N2 O S: C, 59.97; H, 5.49; N, 12.72. Found: C, 59.67; H, 5.35; N, 12.70. Mass spectrum (EI, M.+) m/z 220. lH-NMR (DMSO-d6; 400 MHz) â 7.43-7.52 (m, 3H), 7.28-7.31 (m, 2H), 4.32 (s, 2H), 3.07 (q, 2H), and 1.27 ppm (t, 3H).
F,XA MPLE 1() 2-Ethylsulfanvl~ f~ oro-2-metllyll)henvl)-3~5-dihydro-imid~,ol-~-~ne A mixture of glycinamide hydrochloride (4.42 g), 5-fluoro-2-methylphenyl-isothiocyanate (6.68 g), triethyl amine (4 1 g), and chloroform (150 mL) was stirred at ambient ~em~ ture for 18 hours. The precipitate was collected by filtration, washed with chloroform and air dried to give 7-~3-(5-Fluoro-2-methylphenyl)-thioureido]-25 ~ce~mi~le (7.6 g), m.p. 172-174 C (dec.). This compound was used without further purification in the next paragraph.

A mixture of 2-[3-(5-fluoro-2-methylphenyl)-thioureido]-acetamide (6.0 g), ethyl iodide (15.6 g), and eth;mol (1'70 mL) was heated at reflux for 4 hours. The 30 solvent was evaporated. The residue was treated with ethyl acetate (400 ml) and filtered. The filtrate was washed with water (30() mL). The organic phase was evaporated to dryness. The residue w;ls dissolved in ethanol. The solution was saturated with hydrogen chloride. The solvent was evaporated and the residue was cryst~lli7~-d from ethyl acetate and dried under v~cuum to give the mono-hydrochlonde .

W O 97/19931 PCTnUS96/19108 of the title compound as a white solid ( 4.2 g), m.p. 181-183 C. Anal. Calcd. for.
C12 H13 F N2 O S . HCI: C, 49.91; H, 4.89; N, 9.70. Found: C, 49.83; H, 4.82; N,9.71. Mass spectrum (+FAB,[M+H~+) m/z 253. lH-NMR (DMSO-d6; 400 MHz) 7.50-8.45 (broad s, 2H), 7.45 (m, lH), 7.27-7.34 (m, 2H), 4.48 (q, 2H), 3.21 (m, 2H), 2.10 (s, 3H), and 1.29 ppm (t, 3H).
l~XA MPLE 11 ;~-(?5-Chloro-2-methylpllellYI)-2-etllylslllf~nyl-3.5-dihydro-imid~ol-1-one A mixture of glycin~mide hydrochloride (6.1 g), 3-chloro-2-methylphenyl-isothiocyanate (10.1 g), triethyl amine (5.6 g), and chlorofonn (200 mL) was heated at reflux for 3 hours then cooled to ambient temperature. The precipitate was collected by 15 filtration, washed with chlorofornl and air dried to give 2-[3-(3-chloro-2-methylphenyl)-thioureido]-acetamide (l'7.5 g), m p. 162-164 C (dec.). This compound was used without further pLIrification for the preparation of the titlecompound of step 2.

The title compound was prepal~d by the procedure described in Example 6 using 12.0 g of 2-[3-(3-chloro-2-methylphellyl)-thioLIreido]-acetamide, and 25.0 g of ethyl iodide. The hydrochloride salt was prep.lred in ethere.ll hydrogen chloride.
Cryst~11i7~tion from ethyl acetate afforded the title compound as a white solid, mono-hydrochloride (5.1 g), m.p. 161-163 C (dec.). An:~l. Calcd. for. C12 H13 Cl N2 0 S
. HCl: C, 47.22; H, 4.62; N, 9.18. Found: C, 47.03; H, 4.40; N, 9.09. Mass spectrum (+FAB, rM+H]+) m/z 769/271. lH-NMR (DMSO-d6; 400 MHz) o 9.05-9.85 (broad s, 2H), 7.62 (d, lH), 7.39 (t, lH), 7.33 (d, lH), 4.48 (q, 2H), 3.20 (m, 2H), 2.15 (s, 3H), and 1.29 ppm (t, 3H).

W O 97/19931 PCT~US96/19108 - 3-(3-Chloro-4-methvlr)henvl)-2-ethvlslllfanvl-3~5-dihydro-imidzlJ.ol-4-one 2-[3-(3-Chloro-4-methylphenyl)-thioureido]-acetamide was prepared by the procedure described Example 11 using 18.36 g of 3-chloro-4-methylphenyl-isothiocyanate, 11.05 g of glycinamide hydrochloride, 10.1 g of triethyl amine, and 300 rnL of chloroform. 22.0 Grams of the desired product was obtained, m.p. 167-169 C (dec.). Mass spectrum (El, M.+) m/z 257/259. lH-NMR (DMSO-d6; 400 MHz) ~9.93 (s, lH), 7.80 (t, lH), 7.73 (s, lH), 7.52 (s, lH), 7.25 (m, 2H), 7.16(s, lH), 4.07 (d, 2H), and 2.27 ppm (s, 3H).

A mixture of 2-[3-(3-chloro-4-methylpllellyl)-thioureido]-acetamide (10.0 g), ethyl iodide (17.5 g), and ethanol (700 mL) was heated at reflux for 2.5 hours. The solvent was evaporated. The residue W;IS dissolved in ethyl acetate (500 rnL) and water (500 rnL). The organic phase was washed with water (2x300 mL). The organic phasewas extracted with 2N HCI (2x500 mL). The acid extract was neutralized with solid sodium bicarbonate and extracted with ethyl acetate. The organic phase was washed 20 with water, dried over anhydrous Na ~SO~ then evapor;lted to dryness. The residue was stirred in diethyl ether and filtered to give the title compound (8.4 g) as a white solid, m.p. 133-135 C. Anal. Calcd. for. Cl2 H13 Cl N2 O S: C, 53.63; H, 4.88;
N,10.42. Found: C, 53.66; H, 4.78; N, 10.39. Mass spectrum (EI, M.+) m/z 268/270. lH-NMR (DMSO-d6; 400 MHz) ~ 7.47 (d, lH), 7.43 (d, lH), 7.20 (dd, lH), 4.29 (s, 2H), 3.07 (q, 2H), 2.36 (s, 3H), and 1.28 ppm (t, 3H).
l~XAMPLE 13 3-(4-Chloro-2-methvlphenvl)-2-etllvl.slllf~nvl-3~5-dihvdro-imicl~ol-4-one 2-t3-(4-Chloro-2-methylphenyl)-thiouleido]-acetamide was prepared by the procedure described in Example 11 using 18.36 g of 4-chloro-2-methylphenyl-isothiocyanate, 11.05 gof glycinamide hydrochloride, 10.1 g of triethyl amine, and 300 rnL of chlorofonn. 21.4 Grams of the desired compound was obtained, m.p. 170-W O 97~19931 PCTrUS96/19108 172~ C (dcc.). Mass spectrum (El, M.+) m/z 257/259. lH-NMR ~DMSO-d6; 400 MHz) ~; 9.38 (s, lH), 7.62 (broad s, IH), 7.45 (s, lH), 7.35 (d, lH), 7.32 (d, lH), 7.21 (m, lH), 7.12 (s, lH), 4.06 (d, 2H), and 2.17 ppm (s, 3H).

Ihe tide col~o~uld was prepared by the procedu~e desr~nbed in ~ - i~ 6 using 18.0 g of 2-[3-(4-chloro-2-methylphenyl)-thioureido]-aeet~mi-le, and 25.0 g of ethyl iodide. The hydrochloride salt was ~ p~ed in ethereal hydrogen chloride.
Cryst~lli7~tion from ethyl acetate afforded the title compound as an off-white solid, mono-hydrochloride (17.6 g), m.p. 166-168~ C (dec.). An~l. Calcd. for. C12 H13 Cl N2 O S . HCI: C, 47.22; H, 4.62; N, 9.18. Found: C, 47.24; H, 4.4~; N, 9.05. Mass ~)Cel~ln (+FAB, rM+H]+) m/z 269/271. IH-NMR (DMSO-d6; 400 MHz) ~ 9.0S-9.78 (broad s, 2H), 7.53 (m, lH), 7.44 (d, lH), 7.41 (d, lH), 7.33 (d, lH), 4.48 (q, 2H), 3.20 (m, 2H), 2.13 (s, 3H), and 1.~9 ppm (t, 3H).

F.XA MPl,E 14 3-(~.6~imethvlDhenyl)-2-ethvl~lllt~nvl-?~.5-dihv~lro-imid~ol 4-orle A rnixture of 2,6-dimethylphenyl-isothiocyanate (16.3 g), glycin~mi~e hydrochloride (11.05 g), triethyl amine (12.0 g), and chloroform (250 mL) was heated at reflux for 3 hours. The solvent was evapora~ed. The residue was dissolved in ethyl acetate (500 mL) and washed with lN HCl (300 mL) then with water (300 mL). The organic phase was eva~o dtcd to dryness, then the residue was stirred with diethyl ether. The solid was collect~d by filtration and dried to afford 2-[3-(2,6-dimethylphenyl)-thioureido]-acetamide as a solid (18.3 g). Mass spectrum (EI, M.+) m/z 237. This co.llpound was used without furlher purification in the ~ I;nn of ~c tide cc,nll,o~ l-d.

The title compound was p.Gpa-~id by the procedure described in l:y~n~r1c 12 using 8.0 g of 2-[3-(2,6-dimethylphenyl)-thiourcido]-acet~mide, 25.0 g of ethyl iodide, and (200 mL) ethanol. Cryst:~1li7~ion from hexane/diethyl ether ~ lu~
f~l~d the tide compound as a light yellow solid (2.4 g), m.p. 86-88~ C. Anal.
Calcd. for. C12 H16 N2 0 S: C, 62.87; H, 6.49; N, 11.28. Found: C, 62.98; H, 6.57; N, 11.30. Mass spectrum (El, M.+) m/2 248. IH-NMR (DMSO-d6; 400 MHz) WO 97/19931 PCT~US96/19108 7.27-7.30 (m, lH), 7.21 (m, lH), 7.19 (m, lH), 7.33 (d, lH), 4.42 (s, 2H), 3.06 (q, 2H), 2.07 (s, 6H), and 1.26 ppm (t, 3H).

Claims

What is claimed is:

(1) A compound of formula I:

wherein R is phenyl or phenyl optionally substituted with one or more groups selected from halogen, alkyl of 1 to 6 carbon atoms, perfluoroalkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, perfluoroalkoxy of 1 to 6 carbon atoms, hydroxy, alkanoyloxy of 2 to 6 carbon atoms, aroyloxy of 7 to 11 carbon atoms or arylalkanoyloxy of 8 to 16 carbon atoms;
R3 is alkyl of 1 to 6 carbon atoms, aryl of 6 to 10 carbon atoms or arylalkyl of7 to 12 carbon atoms;
or a pharmaceutically acceptable salt thereof.

(2) A compound of formula 1:

wherein R is phenyl or phenyl optionally substituted with one or more groups selected from halogen, alkyl of 1 to 3 carbon atoms, perfluoromethyl, alkoxy of 1 to 3 carbon atoms, perfluoromethoxy, hydroxy or alkanoyloxy of 2 to 4 carbon atoms;
R3 is alkyl of 1 to 3 carbon atoms or arylalkyl or 7 to 9 carbon atoms;
or a pharmaceutically acceptable salt thereof.

(3) The compound of Claim 1 which is 2-ethylsulfanyl-3-(4-fluorophenyl)-3,5-dihydro-imidazol-4-one or a pharmaceutically acceptable salt thereof.

(4) The compound of Claim 1 which is 3-(5-chloro-2-methylphenyl)-2-ethylsulfanyl-3,5-dihydro-imidazol-4-one or a pharmaceutically acceptable salt thereof.

(5) The compound of Claim 1 which is 3-(5-chloro-2-methoxyphenyl)-2-ethylsulfanyl-3,5-dihydro-imidazol-4-one or a pharmaceutically acceptable salt thereof.

(6) The compound of Claim 1 which is 3-(2,6-dichlorophenyl)-2-ethylsulfanyl-3,5-dihydro-imidazol-4-one or a pharmaceutically acceptable salt thereof.

(7) The compound of Claim 1 which is 2-benzylsulfanyl-3-(5-chloro-2-methylphenyl)-3,5-dihydro-imidazol-4-one or a pharmaceutically acceptable salt thereof.

(8) The compound of Claim 1 which is 3-(2-chlorophenyl)-2-ethylsulfanyl-3,5-dihydro-imidazol-4-one or a pharmaceutically acceptable salt thereof.

(9) The compound of Claim 1 which is 2-ethylsulfanyl-3-(2-tolyl)-3,5-dihydro-imidazol-4-one or a pharmaceutically acceptable salt thereof.

(10) The compound of Claim 1 which is 3-(2-chloro-6-methylphenyl)-2-ethylsulfanyl-3,5-dihydro-imidazol-4-one or a pharmaceutically acceptable salt thereof.

(11) The compound of Claim 1 which is 2-ethylsulfanyl-3-phenyl-3,5-dihydro-imidazol-4-one or a pharmaceutically acceptable salt thereof.

(12) The compound of Claim 1 which is 3-(2,6-dimethylphenyl)-2-ethylsulfanyl-3,5-dihydro-imidazol-4-one or a pharmaceutically acceptable salt thereof.

(13) A compound of Claim 1 which is 2-ethylsulfanyl-3-(5-fluoro-2-methylphenyl)-3,5 dihydro-imidazol-4-one or a pharmaceutically acceptable salt thereof.

(14) A compound of Claim 1 which is 3-(3-chloro-2-methylphenyl)-2-ethylsulfanyl-3,5-dihydro-imidzol-4-one or a pharmaceutically acceptable salt thereof.

(15) A compound of Claim 1 which is 3-(3-chloro-4-methylphenyl)-2-ethylsulfanyl-3,5-dihydro-imidazol-4-one or a pharmaceutically acceptable salt thereof.

(16) A compound of Claim 1 which is 3-(4-chloro-2-methylphenyl)-2-ethylsulfanyl-3,5-dihydro-imidazol-4-one or a pharmaceutically acceptable salt thereof.

(17) A process for preparing a compound of formula I or a pharmaceutical by acceptable salt thereof which comprises:
a) reacting a 2-thioxo-imidazolidin-4-one of formula (A):

wherein R is as defined in Claim 1 with methyl iodide to give a corresponding compound of formula I wherein R3 is methyl, or b) reacting a thiourea amide of formula 3:

wherein R is as defined in Claim 1 with a compound of formula:

R3~X

(18) A compound of formula 1 as defined in any one of Claims 1 to 16 or a pharmaceutically acceptable salt thereof for use as a pharmaceutical.

(19) Use of a compound of formula I as defined in Claim 1 or a pharmaceuticallyacceptable salt thereof, for the manufacture of a medicament for increasing blood serum HDL cholesterol levels in a mammal.

(20) Use of the compound 3-(5-chloro-2-methylphenyl)-2-ethylsulfanyl-3,5-dihydro-imidazol-4-one or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for increasing blood serum HDL cholesterol levels in a mammal.

(21) Use of the compound 3-(2,6-dichlorophenyl)-2-ethylsulfanyl-3,5-dihydro-imidazol-4-one or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for increasing blood serum HDL cholesterol levels in a mammal.

(22) Use of the compound 2-benzylsulfanyl-3-(5-chloro-2-methylphenyl)-3,5-dihydro-imidazol-4-one or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for increasing blood serum HDL cholesterol levels in a mammal.

(23) Use of the compound 2-ethylsulfanyl-3-(2-tolyl)-3,5-dihydro-imidazol-4-one or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for increasing blood serum HDL cholesterol levels in a mammal.

(24) A method for increasing blood serum HDL cholesterol level in a mammal which comprises administering to said mammal an effective amount of a compound as claimed in any one of Claims 1 to 16.