Background Art The acyl-coenzyme A: cholesterol 0-acyltransferase (EC 2.3.1.26) (ACAT) enzyme is responsible for the catalysis of the intracellular esterification of cholesterol.

ACAT is present in most tissues such as the intestine, liver, and arterial wall. The enzyme is assumed to be involved in numerous processes which underlie the development of atherosclerosis, absorption of dietary cholesterol, accumulation of cholesterol esters, hepatic secretion of cholesterol esters into the blood plasma in the form of VLDL cholesterol.

A number of substances of the urea type have been described to inhibit ACAT.

We shall show several more, recent examples describing 1,3-disubstituted ureas as ACAT enzyme inhibitors. Patents EP 506532, FR 2674522, JP 93097802, US 5219859 describe ureas containing indole derivatives in their molecules. A combination of aromatic and aliphatic moieties has been described in Patents EP 665216, JP 95258199. Introduction into the molecule of a 1,3-dioxolane ring has been reported in Bioorg. Med. Chem. Lett. 1995,5 (15): 1581.

1,3-Disubstituted ureas of the present invention have not been described in literature.

Disclosure of Invention 1,3-Disubstituted ureas of general formula I wherein R'is 4-nitrophenyl, 2-fluorophenyl, 4-fluorophenyl, 2,4-difluorophenyl, 2,5-difluorophenyl, 2,6-difluorophenyl, 2-chlorophenyl, 4-chlorophenyl, 2,3- dichlorophenyl, 2,4-dichlorophenyl, 2,6-dichlorophenyl, 3,4-dichlorophenyl, 3,5- dichlorophenyl, 2-methylphenyl, 4-methylphenyl, 2,4-dimethylphenyl, 2,6- dimethylphenyl, 3,5-dimethylphenyl, 2,6-di (methylethyl) phenyl, 2-trifluoromethyl- phenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 2-pyridyl, 3-pyridyl, 4- pyridyl, 1-naphthyl, 2-naphthyl, 1-adamantyl, and R2 is nitro, and X = 0, S; and for R'being 2,4-difluorophenyl, 2,3-dichlorophenyl, 2,6-dimethylphenyl, 2,6-di- (methylethyl)-phenyl R2 is amino, and X = 0, S.

The method for the preparation of the above compounds according to this invention consists in reacting an isocyanate (as prepared in situ or as commercially available) with amine to give an urea the nitro group of which may subsequently be reduced to the amino group. Ureas prepared in this way show inhibitory effect on acyl-coenzyme A: cholesterol acyltransferase (ACAT).

Examples Example 1 1- (4-Nitrophenyl)-3- ( (-4'nitrophenoxy)-phenyl)-urea A solution of 4-nitrophenylisocyanate in diethylether (20 ml) is added dropwise to a solution of 4'-nitrophenoxy-aniline (2.30 g, 0.01 mol) in a mixture of diethylether (20 ml) and tetrahydrofurane (20 ml) at laboratory temperature, and the mixture is stirred for 16 hours. The precipitated product is aspirated, washed with diethylether (20 ml). The raw product is purified by chromatography on silica gel eluting with dichloromethane-methanol.

'H-NMR (CDCI3): 7.11 (d, 2H, H-arom.); 7.17 (d, 2H, H-arom.); 7.59 (d, 2H, H- arom.); 7.70 (d, 2H, H-arom.); 8.20 (d, 2H, H-arom.); 7.25 (d, 2H, H-arom.); 9.05 (s, 1H, NH.); 9.46 (s, 1H, NH).

'3C-NMR (CDCI3); 116.80 (CH-arom.); 117.46 (CH-arom.); 120.46 (CH-arom.); 121.13 (CH-arom.) ; 125.07 (CH-arom.); 126.11 (CH-arom.) ; 136.50,141.00, (C-arom.); 163.39 (C=0).

Analysis for C, 9H, 4N406 % C (calcd/found) % H % N 57.85/57.73 3. 58/3.61 14.21/14.12 I Yield: 92% Melting temp.: 231-234°C Example 2 1- (2-Fluorophenyl)-3- ( (4'-nitrophenoxy)-phenyl)-urea The title compound was prepared from 2-fluorophenylisocyanate by an analogous procedure to that described in Example 1.

Analysis for CagH14FN304 % C (calcd/found) % H % N 88 11.44/11.29 Yield: 48% Melting temp.: 253-255°C Example 3 1-(4-Fluorophenyl)-3-((4'-nitrophenoxy)-phenyl)-urea The title compound was prepared from 4-fluorophenylisocyanate by an analogous procedure to that described in Example 1.

Analysis for C18H14FN3O4 | % C 62.11/61.99 3.44/11.34 Yield: 59% Melting temp.: 267-269°C Example 4 1- (2, 4-Difiuorophenyl)-3- ( (4'-nitrophenoxy)-phenyl)-urea The title compound was prepared from 2,4-difluorophenylisocyanate by an analogous procedure to that described in Example 1.

'H-NMR (CDCl3) : 6.98-7.18 (m, 5H, H-arom.); 7.23-7.37 (m, 1H, H-arom.); 7.56 (d, 2H, H-arom.); 8.03-8.16 (m, 1H, H-arom.); 8.24 (d, 2H, H-arom.); 8.50 (s, 1 H, NH); 9.13 (s, 1 H, NH).

3C-NMR (CDCl3) : 103.72 (CH-arom.); 110.96 (CH-arom.); 116.73 (CH-arom.); 119.88 (CH-arom.); 121.18 (CH-arom.); 122.02 (CH-arom.); 126.09 (CH-arom.); 136.94,141.91,148.48,152.27,154.49,159.80 (C-arom.); 163.46 (C=0).

Analysis for C, 9H,3F2N304 % C (calcd/found) % H % N 53 10.91/10.89 Yield: 85% Melting temp.: 223-224°C Example 5 1- (2, 5-Difluorophenyl)-3- ( (4'-nitrophenoxy)-phenyl)-urea The title compound was prepared from 2,5-difluorophenylisocyanate by an analogous procedure to that described in Example 1.

'H-NMR (CDCl3) : 6.73-6.88 (m, 1 H, H-arom.); 7.04-7.35 (m, 5H, H-arom.); 7.56 (d, 2H, H-arom.); 7.98-8.11 (m, 1H, H-arom.); 8.22 (d, 2H, H-arom.); 8.75- 9.30 (br. s., 2H, NH).

3C-NMR (CDC13): 106.56 (CH-arom.); 107.75 (CH-arom.); 115.67 (CH-arom.); 116.74 (CH-arom.); 120.03 (CH-arom.); 121.21 (CH-arom.); 126.08 (CH-arom.); 128.82,136.62,141.95,148.73,151.95,155.65,160.38 (C-arom.); 163.42(C=O).

Analysis for C1gH13F2N304 % C (calcd/found) % H % N 59.22/59.0710.91/10.83 Yield: 76% Melting temp.: 207-208°C Example 6 1- (2, 6-Difluorophenyl)-3- ( (4'-nitrophenoxy)-phenyl)-urea The title compound was prepared from 2,6-difluorophenylisocyanate by an analogous procedure to that described in Example 1.

'H-NMR (CDC13): 6.95-7.26 (m, 6H, H-arom.); 7.42-7.56 (m, 2H, H-arom.); 8.01- 8.23 (m, 3H, H-arom.); 8.94-9.05 (m, 2H, NH).

'3C-NMR (CDCI3): 111.77 (CH-arom.); 116.82 (CH-arom.); 120.06 (CH-arom.); 121.18 (CH-arom.); 126.19 (CH-arom.); 127.11 (CH-arom.); 137.31,141.99, 148.49,152.61,155.65,160.57 (C-arom.); 163.61 (C = O).

Analysis for C19H13F2N3O4 % C (calcd/found) % H % N 59.22/59. 10 3. 40/3.55 10.91/10.78 I Yield: 75% Melting temp.: 231-232°C Example 7 1- (2-Chlorophenyl)-3- ( (4'-nitrophenoxy)-phenyl)-urea The title compound was prepared from 2-chlorophenylisocyanate by an analogous procedure to that described in Example 1.

Analysis for C19H14CIN304 % C (calcd/found) % H % N % CI 82 10. 95/10.78 9.24/8.99 Yield: 63% Melting temp.: 195-197°C Example 8 1- (4-Chlorophenyl)-3- ( (4'-nitrophenoxy)-phenyl)-urea The title compound was prepared from 4-chlorophenylisocyanate by an analogous procedure to that described in Example 1.

Analysis for C19H14ClN3O4 % C (calcd/found) % H % N % CI 77 10.95/10.84 9.24/9.02 Yield: 69% Melting temp.: 234-236°C Example 9 1-(2,3-Dichlorophenyl)-3-((4'-nitrophenoxy)-phenyl)-urea The title compound was prepared from 2,3-dichlorophenylisocyanate by an analogous procedure to that described in Example 1.

Analysis for C19H13Cl2N3O4 %C (calcd/found) | %H| %N| %CI 54.56/54.50 3.13/3. 10. 05/9.78 16.95/16.91 Yield: 74% Melting temp.: 199-201 °C Example 10 1- (2, 4-Dichlorophenyl)-3- ( (4'-nitrophenoxy)-phenyl)-urea The title compound was prepared from 2,4-dichlorophenylisocyanate by an analogous procedure to that described in Example 1.

Analysis for C19H'3CI2N304 % C (calcd/found) % H % N % CI 21 10.05/9.80 16.95/16.59 Yield: 71 % Melting temp.: 267-269°C Example 11 1- (2, 6-Dichlorophenyl)-3- ( (4'-nitrophenoxy)-phenyl)-urea The title compound was prepared from 2,6-dichlorophenylisocyanate by an analogous procedure to that described in Example 1.

Analysis for C19H'3CI2N304 % C (calcd/found) % H % N % CI 54.56/54. 39 3. 13/3.20 10.05/9.92 16.95/16.81 Yield: 68% Melting temp.: 195-198°C Example 12 1-(3,4-Dichlorophenyl)-3-((4'-nitrophenoxy)-phenyl)-urea The title compound was prepared from 3,4-dichlorophenylisocyanate by an analogous procedure to that described in Example 1.

Analysis for C19H13Cl2N3O4 % C (calcd/found) % H % N % CI 23 10.05/9.89 16.95/16.78 Yield: 80% Melting temp.: 179-180°C Example 13 1-(3,5-Dichlorophenyl)-3-((4'-nitrophenoxy)-phenyl)-urea The title compound was prepared from 3,5-dichlorophenylisocyanate by an analogous procedure to that described in Example 1.

Analysis for C19H'3CI2N304 % C (calcd/found) % H % N % CI 30 10.05/10.01 16.95/17.24 Yield: 56% Melting temp.: 213-216°C Example 14 1- (2-Methylphenyl)-3- ( (4'-nitrophenoxy)-phenyl)-urea The title compound was prepared from 2-methylphenylisocyanate by an analogous procedure to that described in Example 1.

Analysis for C2oH"N304 % C (calcd/found) % H % N 89 11.56/11.48 Yield: 59% Melting temp.: 112-116°C Example 15 1- (4-Methylphenyl)-3- ( (4'-nitrophenoxy)-phenyl)-urea The title compound was prepared from 4-methylphenylisocyanate by an analogous procedure to that described in Example 1.

Analysis for C2oH"N304 %C (calcd/found) % H % N 87 11.56/11.40 Yield: 64% Melting temp.: 168-170°C Example 16 1-(2, 4-Dimethylphenyl)-3-((4-nitrophenoxy)-phenyl)-urea The title compound was prepared from 2,4-dimethylphenylisocyanate by an analogous procedure to that described in Example 1.

Analysis for C21H19N3O4 % C (calcd/found) % H % N 10 11.13/11.05 Yield: 73% Melting temp.: 165-169°C Example 17 1-(2, 6-Dimethylphenyl)-3-((4-nitrophenoxy)-phenyl)-urea The title compound was prepared from 2,6-dimethylphenylisocyanate by an analogous procedure to that described in Example 1.

'H-NMR (CDC13): 2.22 (s, 6H, CH3) ; 7.04-7.17 (m, 7H, H-arom.); 7.57 (m, 2H, H- arom.); 7.74 (s, 1H, NH); 8.23 (d, 2H, H-arom.); 8.87 (s, 1H, NH).

'3C-NMR (CDCl3) : 18.19 (2x CH3); 116.61 (CH-arom.); 119. 54 (CH-arom.); 121.08 (CH-arom.); 126.07 (CH-arom.); 127.67 (CH-arom.); 135.53 (CH-arom.); 125.93,135.51,137,95,141.82,147,87,153.10 (CH-arom.); 163.64 (C=0).

Analysis for C2, H,gN304 %C (calcd/found) % H % N 18 11.13/10.98 Yield: 68% Melting temp.: 249-250°C Example 18 1-(3, 5-Dimethyiphenyl)-3-((4'-nitrophenoxy)-phenyl)-urea The title compound was prepared from 3,5-dimethylphenylisocyanate by an analogous procedure to that described in Example 1.

Analysis for C21H1gN304 % C (calcd/found) % H % N 66.83/66.785.07/5.22 11.13/11.06 Yield: 58% Melting temp.: 145-147°C Example 19 1- (2, 6-Di- (methylethyl)-phenyl)-3- ( (4'-nitrophenoxy)-phenyl)-urea The title compound was prepared from 2,6-di- (methylethyl) phenylisocyanate by an analogous procedure to that described in Example 1.

'H-NMR (CDCl3) : 1.18 (d, 6H, 2xCH3); 3.22 (hept., 2H, 2xCH); 7.06-7.30 (m, 7H, H-arom.); 7.56 (d, 2H, H-arom.); 7.63 (s, 1H, NH); 8.23 (d, 2H, H-arom.); 8.78 (s, 1H, NH).

'3C-NMR (CDC13): 23.31 (2xCH3); 116.58 (CH-arom.); 119.44 (CH- arom.); 120.86 (CH-arom.); 122.72 (CH-arom.); 125.87 (CH-arom.); 146.53 (CH- arom.); 127.08,132.14,137.80,141.83,147.89,154.10 (C-arom.); 163.46 (C = 0).

Analysis for C25H27N304 %C (calcd/found) % H % N 34 9.69/9.56 Yield: 88% Melting temp.: 208-210°C Example 20 1- (2-Trifluoromethylphenyl)-3- ( (4'-nitrophenoxy)-phenyl)-urea 4'-Nitrophenoxy-aniline (1.0 g, 4.3 mmol), triphosgene (0.43 g, 1.44 mmol), triethylamine (0.6 ml, 4.3 mmol) are heated in toluene (15 ml) in a pressure tube at 80°C for 20 hours. Then, 2-trifluoromethylaniline (0.53 ml, 4.3 mmol) and triethylamine (0.6 ml, 4.3 mmol) in toluene (10 ml) are added. The mixture is heated at 80°C for 4 hours, then it is concentrated, and the product is isolated using chromatography on silica gel eluting with dichloromethane-methanol.

Analysis for C2oH,4F3N304 %C (calcd/found) | %H| %N 44 10.07/9.89 Yield: 67% Melting temp.: 201-203°C Example 21 1- (3-Trifluoromethylphenyl)-3- ( (4'-nitrophenoxy)-phenyl)-urea The title compound was prepared from 3-trifluoromethylaniline by an analogous procedure to that described in Example 20.

Analysisfor C20H'4F3N304 % C (caicd/found) % H % N 57.56/57. 66 3.38/3. 45 10.07/9.96 Yield: 72% Melting temp.: 208-211 °C Example 22 1-(4-Trifluoromethylphenyl)-3-((4'-nitrophenoxy)-phenyl)-ure a The title compound was prepared from 4-trifluoromethylaniline by an analogous procedure to that described in Example 20.

Analysisfor C2oH,4F3N304 %N%C(calcd/found)%H 57.56/57.483.38/3.41 10.07/10.00 Yield: 45% Melting temp.: 185-189°C Example 23 1- (2-Pyridyl)-3- (4'-nitrophenoxy)-phenyl)-urea The title compound was prepared from 2-pyridylamine by an analogous procedure to that described in Example 20.

Analysis for C18H14N4O4 %C (calcd/found) % H % N 61.71/61.67 4. 03/4.06 15.99/15.79 I Yield: 76% Melting temp.: 143-146°C Example 24 1- (3-Pyridyl)-3- (4'-nitrophenoxy)-phenyl)-urea The title compound was prepared from 3-pyridylamine by an analogous procedure to that described in Example 20.

Analysis for C18H14N4O4 % C (calcd/found) % H % N 15.99/15.8761.71/61.584.03/4.21 Yield: 69% Melting temp.: 177-179°C Example 25 1- (4-Pyridyl)-3- (4'-nitrophenoxy)-phenyl)-urea The title compound was prepared from 4-pyridylamine by an analogous procedure to that described in Example 20.

Analysis for C18H14N4O4 % C (calcd/found) % H % N 11 15.99/15.87 Yield: 72% Melting temp.: 126-127°C Example 26 1- (1-Naphthyl)-3- (4'-nitrophenoxy)-phenyl)-urea The title compound was prepared from 1-naphthylisocyanate by an analogous procedure to that described in Example 1.

Analysis for C23H"N304 %N%C(calcd/found)%H 69.17/69.23 4.29/4.41 10.52/10.46 Yield: 82% Melting temp.: 117-119°C Example 27 1- (2-Naphthyl)-3- (4'-nitrophenoxy)-phenyl)-urea The title compound was prepared from 1-naphthylamine by an analogous procedure to that described in Example 20.

Analysis for C23H17N304 %N%C(calcd/found)%H 69.17/69.094. 29/4.29/4.10.52/10.38 Yield: 69% Melting temp.: 103-106°C Example 28 1- (1-Adamantyl)-3- (4'-nitrophenoxy)-phenyl)-urea The title compound was prepared from 1-adamantylamine by an analogous procedure to that described in Example 20.

Analysis for C23H25N304 % C (calcd/found) % H % N 67.80/67. 65. 6. 18/6.23 10.31/10.16 I Yield: 61 % Melting temp.: 143-146°C Example 29 1- (4-Nitrophenyl)-3- ( (4'-nitrophenylthio)-phenyl)-urea A solution of 4-nitrophenylisocyanate in diethylether (20 ml) is added dropwise to a solution of 4'-nitrophenylthio-aniline (2.46 g, 0.01 mol) in a mixture of diethyelther (20 ml) and tetrahydrofurane (20 ml) at laboratory temperature, and the mixture is stirred for 16 hours. The resulting product is aspirated, washed with diethylether (20 ml). The crude product is purified by chromatography on silica gel eluting with dichloromethane and methanol.

Analysis for C19H14N405S % C 55.61/55. 52. 3. 44/3.49 13.65/13.59 7.81/7.67 Yield: 56% Melting temp.: 164-167°C Example 30 1- (2-Fluorophenyl)-3- ( (4'-nitrophenylthio)-phenyl)-urea The title compound was prepared from 2-fluorophenylisocyanate by an analogous procedure to that described in Example 29.

Analysis for C, 9H, QFN303S % C (calcd/found) % H % N S% 10.96/11.96/11.8.36/8.36/8.

Yield: 61 % Melting temp.: 274-277°C Example 31 1- (4-Fluorophenyl)-3- ( (4'-nitrophenylthio)-phenyl)-urea The title compound was prepared from 4-fluorophenylisocyanate by an analogous procedure to that described in Example 29.

Analysis for C19H14FN303S %C (calcd/found) % H % N S% 59. 52/59. 46 3.68/3.10.96/10.87 8.36/8.18 Yield: 59% Melting temp.: 287-290°C Example 32 1-(2, 4-Difluorophenyl)-3-((4-nitrophenylthio)-phenyl)-urea The title compound was prepared from 2,4-difluorophenylisocyanate by an analogous procedure to that described in Example 29.

Analysis for C19H13F2N3O3S % C (calcd/found) % H % N S% 10.47/10.41 7.99/7.86 Yield: 57% Melting temp.: 268-271 °C Example 33 1- (2, 5-Difluorophenyl)-3- ( (4'-nitrophenylthio)-phenyl)-urea The title compound was prepared from 2,5-difluorophenylisocyanate by an analogous procedure to that described in Example 29.

Analysis for C19H13F2N3O3S %NS%%C(calcd/found)%H 56.86/56. 76 3.26/3.37 10.47/10. 35 7.99/8.05 Yield: 64% Melting temp.: 259-261 °C Example 34 1-(2,6-Difluorophenyl)-3-((4'-nitrophenylthio)-phenyl)-urea The title compound was prepared from 2, 6-difluorophenylisocyanate by an analogous procedure to that described in Example 29.

Analysis for C19H13F2N3O3S % C (calcd/found) % H % N S% 56.86/56. 69 3.26/3. 34 10.47/10.43 7.99/7.81 Yield: 68% Melting temp.: 263-265°C Example 35 1- (2-Chlorophenyl)-3- ( (4'-nitrophenylthio)-phenyl)-urea The title compound was prepared from 2-chlorophenylisocyanate by an analogous procedure to that described in Example 29.

Analysis for C19H14ClN3O3S %N%ClS%%C(calcd/found)%H 57.07/57. 01 3.53/3. 62 10.51/11.46 8.87/8.65 8.02/7.95 Yield: 65% Melting temp.: 231-233°C Example 36 1-(4-Chlorophenyl)-3-((4'-nitrophenylthio)-phenyl)-urea The title compound was prepared from 4-chlorophenylisocyanate by an analogous procedure to that described in Example 29.

Analysis for CiaHi4CIN303S %N%ClS%%C(calcd/found)%H 10.51/10.45 8.87/8.81 8.02/7.86 Yield: 63% Melting temp.: 206-209°C Example 37 1- (2, 3-Dichlorophenyl)-3- ( (4'-nitrophenylthio)-phenyl)-urea The title compound was prepared from 2,3-dichlorophenylisocyanate by an analogous procedure to that described in Example 29.

Analysis for C19H13Cl2N3O3S %N%ClS%%C(calcd/found)%H 52.55/52. 46 3. 02/3.07 9.68/9.62 16.33/16.27 7.38/7.50 I Yield: 75% Melting temp.: 157-159°C Example 38 1-4-Dichlorophenyl)-3-((4'-nitrophenylthio)-phenyl)-urea The title compound was prepared from 2,4-dichlorophenylisocyanate by an analogous procedure to that described in Example 29.

Analysis for C19H13CI2N303S % C (calcd/found) % H % N % CI S% 21 9.68/9.54 16.33/16.35 7.38/7.28 Yield: 57% Melting temp.: 174-178°C Example 39 1-(2,6-Dichlorophenyl)-3-((4'-nitrophenylthio)-phenyl)-urea The title compound was prepared from 2,6-dichlorophenylisocyanate by an analogous procedure to that described in Example 29.

Analysis for C,9H,3CI2N303S | % C 52.55/52.51 3.02/3.07 9.68/9.73 16.33/16.25 7.38/7.19@ Yield: 83% Melting temp.: 164-167°C Example 40 1- (3, 4-Dichlorophenyl)-3- ( (4'-nitrophenylthio)-phenyl)-urea The title compound was prepared from 3,4-dichlorophenylisocyanate by an analogous procedure to that described in Example 29.

Analysis for C, gH, 3CI2N3OgS % C (calcd/found) % H % N %Cl S% 52.55/52. 47 3. 02/3.14 9.68/9.57 16.33/16.09 7.38/7.24 Yield: 57% Melting temp.: 238-240°C Example 41 1- (3, 5-Dichlorophenyl)-3- ( (4'-nitrophenylthio)-phenyl)-urea The title compound was prepared from 3,5-dichlorophenylisocyanate by an analogous procedure to that described in Example 29.

Analysis for C19H13Cl2N3O3S % C (calcd/found) % H % N % CI S% 11 9.68/9.59 16.33/16.21 7.38/7.41 Yield: 67% Melting temp.: 185-188°C Example 42 1-(2-Methylphenyl)-3-((4'-nitrophenylthio)-phenyl)-urea The title compound was prepared from 2-methylphenylisocyanate by an analogous procedure to that described in Example 29.

Analysis for C20H17N3O3S %NS%%C(calcd/found)%H 63.31/63.2263.31/63.224.52/4.66 11.07/10.79 8.45/8.34 Yield: 78% Melting temp.: 229-234°C Example 43 1- (4-Methylphenyl)-3- ( (4'-nitrophenylthio)-phenyl)-urea The title compound was prepared from 4-methylphenylisocyanate by an analogous procedure to that described in Example 29.

Analysis for C20H17N3O3S %NS%%C(calcd/found)%H 63.31/63.2563.31/63.254.52/4.63 11.07/11.12 8.45/8.35 Yie,: 73% Melting temp.: 163-166°C Example 44 1-(2, 4-Dimethylphenyl)-3-((4-nitrophenylthio)-phenyl)-urea The title compound was prepared from 2,4-dimethylphenylisocyanate by an analogous procedure to that described in Example 29.

Analysis for C2, H, 9N303S % C (calcd/found) % H % N S% 83 10.68/10.59 8.15/7.95 Yield: 65% Melting temp.: 209-213°C Example 45 1-(2,6-Dimethylphenyl)-3-((4'-nitrophenylthio)-phenyl)-urea The title compound was prepared from 2,6-dimethylphenylisocyanate by an analogous procedure to that described in Example 29.

Analysis for C2, H, 9N303S % C (calcd/found) % H % N S% 83 10.68/10.47 8.15/8.01 Yield: 72% Melting temp.: 264-267°C Example 46 1-(3, 5-Dimethylphenyl)-3-((4-nitrophenylthio)-phenyl)-urea The title compound was prepared from 3,5-dimethylphenylisocyanate by an analogous procedure to that described in Example 29.

Analysis for C2, H, 9N303S % C (calcd/found) % H % N S% 99 10.68/10.63 8.15/8.01 Yield: 68% Melting temp.: 194-196°C Example 47 1- (2, 6-Dimethylethyl)-phenyl- ( (4'-nitrophenylthio)-phenyl)-urea The title compound was prepared from 2,6- (methylethyl)-phenylisocyanate by an analogous procedure to that described in Example 29. Analysis for C25H27N303S %NS%%C(calcd/found)%H 66.79/66.72 6.06/6.17 9.35/9.27 7.12/6.96 Yield: 72% Melting temp.: 175-177°C Example 48 1-(2-Trifluoromethylphenyl)-3-((4'-nitrophenylthio)-phenyl)- urea 4'-Nitrophenylthio-aniline (1.06 g, 4.3 mmol), triphosgene (0.43 g, 1.44 mmol), triethylamine (0.6 g, 4.3 mmol) in toluene (15 ml) are heated in a pressure tube at 80°C for 20 hours. Subsequently, 2-trifluoromethylaniline (0.53 ml, 4.3 mmol) and triethylamine (0.6 ml, 4.3 mmol) in toluene (10 ml) are added. The mixture is heated at 80°C for 4 hours, then concentrated, and the product is separated by chromatography on silica gel eluting with dichloromethane-methanol.

Analysis for C20H14F3 N303S %NS%%C(calcd/found)%H 39 9.70/9.71 7.40/7.35 Yield: 52% Melting temp.: 257-261 °C Example 49 1- (3-Trifluoromethylphenyl)-3- ( (4'-nitrophenylthio)-phenyl)-urea The title compound was prepared from 3-trifluorophenylisocyanate by an analogous procedure to that described in Example 48.

Analysis for C20H14F3N3O3S % C (calcd/found) % H % N S% 38 9.70/9.53 7.40/7.31 Yield: 65% Melting temp.: 241-244°C Example 50 1- (4-Trifluoromethylphenyl)-3- ( (4'-nitrophenylthio)-phenyl)-urea The title compound was prepared from 4-trifluorophenylisocyanate by an analogous procedure to that described in Example 48.

Analysis for C2oH, 4F3 N303S %C (caicd/found) % H % N S% 55.43/55.3755.43/55.373.26/3.33 9.70/9.81 7.40/7.28 Yield: 51 % Melting temp.: 254-257°C Example 51 1- (2-Pyridyl)-3- ( (4'-nitrophenylthio)-phenyl)-urea The title compound was prepared from 2-pyridylamine by an analogous procedure to that described in Example 48.

Analysis for C18H14N4O3S % C (calcd/found) % H % N S% 91 15.29/15.23 8.75/8.80 Yield: 48% Melting temp.: 278-281 °C Example 52 1-(3-Pyridyl)-3-((4'-nitrophenylthio)-phenyl)-urea The title compound was prepared from 3-pyridylamine by an analogous procedure to that described in Example 48.

Analysis for C18H14N4O3S % C (calcd/found) % % N S% 59.01/58. 99 3.85/3. 99 15.29/15.25 8.75/8.49 Yield: 63% Melting temp.: 261-264°C Example 53 1- (4-Pyridyl)-3- ( (4'-nitrophenylthio)-phenyl)-urea The title compound was prepared from 4-pyridylamine by an analogous procedure to that described in Example 48.

Analysis for C18H14N4O3S %C(calcd/found) S%%N 59.01/58. 92 3. 85/3.76 15.29/15.32 8.75/8.67 Yield: 69% Melting temp.: 190-192°C Example 54 1-(1-Naphthyl)-3-((4'-nitrophenylthio)-phenyl)-urea The title compound was prepared from 1-naphthylisocyanate by an analogous procedure to that described in Example 29. Analysis for C23Hi7N303S %C (calcd/found) % H % N S% 66.49/66.5366.49/66.534.13/4.21 10.12/10.17 7.70/7.54 Yield: 56% Melting temp.: 164-168°C Example 55 1- (2-Naphthyl)-3- ( (4'-nitrophenylthio)-phenyl)-urea The title compound was prepared from 2-naphthylamine by an analogous procedure to that described in Example 48.

Analysis for C23H"N303S % C (calcd/found) % H % N S% 66.49/66.4766.49/66.474.13/4.25 7.70/7.57 Yield: 69% Melting temp.: 142-147°C Example 56 1-(1-Adamantyl)-3-((4-nitrophenylthio)-phenyl)-urea The title compound was prepared from 1-adamantylamine by an analogous procedure to that described in Example 48.

Analysis for C23H25N303S %C (calcd/found) % H % N S% 65.22/65. 17 5. 95/6.03 38 Yield: 52% Melting temp.: 264-267°C Example 57 1- (2,4-Difluorophenyl)-3- ( (4'-aminophenoxy)-phenyl)-urea One gram of compound 4 is dissolved in methanol (20 ml) and 0.1 g of 10% palladium on charcoal is added. The mixture is stirred under hydrogen atmosphere (at atmospheric pressure) for 20 hours. Subsequently, 100 ml methanol is added and the catalyst is removed by filtering. The product is then obtained by concentrating the methanolic solution.

Analysis for C, 9H, 5F2 N302 % C (calcd/found) % H % N 29 11.83/12.01 Yield: 88% Melting temp.: 248-251 °C Example 58 1-(2,5-Dichlorophenyl)-3-((4'-aminophenoxy)-phenyl)-urea The title compound was prepared from compound 9 by an analogous procedure to that described in Example 57.

Analysis for C, 9H, 5C12 N302 %C (calcd/found) % H % N % CI 94 10.82/10.78 18.26/18.11 Yield: 91% Melting temp.: 201-204°C Example 59 1- (2, 6-Dimethylphenyl)-3- ( (4'-aminophenoxy)-phenyl)-urea The title compound was prepared from compound 17 by an analogous procedure to that described in Example 57.

Analysis for C2, H21 N302 % C (calcd/found) % H % N 13 12.10/12.02 I Yield: 85% Melting temp.: 225-227°C Example 60 1- (2,6-Di(methylethyl)-phenyl)-3- ( (4'-aminophenoxy)-phenyl)-urea The title compound was prepared from compound 19 by an analogous procedure to that described in Example 57.

'H-NMR (CDC13): 1.15 (d, 6H, 2xCH3); 3.15 (hept., 2H, 2xCH); 4.86 (s, 2H, NH); 6.57 (d, 2H, H-arom.); 6.72 (d, 2H, H-arom.); 6.81 (d, 2H, H-arom.); 7.10- 1.28 (m, 3H, H-arom.); 7.36 (d, 2H, H-arom.); 7.56 (s, 1 H, HN); 8.58 (br. s., 1 H, NH).

'3C-NMR (CDC13): 23.43 (2xCH3); 27.93 (2xCH); 117.55 (CH- arom.); 119.09 (CH-arom.); 199.43 (CH-arom.); 122.79 (CH-arom.); 127.11 (CH- arom.); 127.11 (CH-arom.); 132.40,134.86,144.77,146.61,146.89, 152.88 (C-arom.); 154.36 (C=O).

Analysis for C25H29N302 % C (calcd/found) % H % N 74.41/74. 54 7. 24/7.33 10.41/10.34 Yield: 90% Melting temp.: 219-221 °C Example 61 1- (2,4-Difiuorophenyl)-3- ( (4'-aminophenylthio)-phenyl)-urea The title compound was prepared from compound 32 by an analogous procedure to that described in Example 57.

Analysis for C, 9H, 5F2 N30S %C (calcd/found) % H % N % S 18 11.31/11.15 8.63/8.51 Yield: 79% Melting temp.: exceeding 300°C Example 62 1- (2, 3-Dichlorophenyl)-3- ( (4'-aminophenylthio)-phenyl)-urea The title compound was prepared from compound 37 by an analogous procedure to that described in Example 57.

Analysis for C, 9H15CI2 N30S %N%Cl%S%C(calcd/found)%H 56.44/56. 35 3. 74/3.80 10.39/10.41 17.54/17.57 7.93/7.59 Yield: 88% Melting temp.: 259-261 °C Example 63 1-(2, 6-Dimethylphenyl)-3-((4-aminophenylthio)-phenyl)-urea The title compound was prepared from compound 45 by an analogous procedure to that described in Example 57.

Analysis for C2, H2, N30S % C (calcd/found) % H % N % S 69.39/69.3269.39/69.325.82/5.93 11.56/11.49 8.28/8.54 Yield: 94% Melting temp.: 198-202°C Example 64 1- (2, 6-Di- (methylethyl)-phenyl-3- ( (4'-aminophenylthio)-phenyl)-urea The title compound was prepared from compound 47 by an analogous procedure to that described in Example 57.

Analysis for C26H29N30S %C (calcd/found) % H % N % S 89 10.01/10.11 7.64/7.58 Yield: 83% Melting temp.: 267-271 °C Tests The biological activity of the substances was evaluated based on the in vitro inhibition of acylCoa: cholesterol acyltransferase (ACAT) activity. The enzyme was obtained from the microsomal fraction of rat liver cells and rabbit intestinal mucosa of animals fed with cholesterol. The substrates for the enzyme reaction included exogenous oleoyl co-enzyme A and endogenous cholesterol.'4C-oleoyl co-enzyme A conversion to'4C-cholesteryl oleate was monitored. From the mixture of extracted lipids, cholesteryl oleate was separated using thin-layer chromatography, and was quantified radiometrically. ACAT specific activity was expressed as the amount of cholesteryl oleate formed per minute per mg microsomal protein.

Table 1 shows percentages of ACAT inhibition in the rat liver and the rabbit intestinal mucosa at various concentrations of the substances tested. Efficiency was calculated as compared to enzyme activity measured in the presence of 1 % dimethylsulfoxide used as the solvent to prepare solutions of the substances tested.

Table 1 Inhibitory effect on rat liver and rabbit intestinal mucosa ACAT activity No Efficiency (%) Concentration No Efficiency (%) Concentration (µMlivermucosa(µM)livermucosa 46233016210 2 2341125232 3 0 24 2 35 20 26 2 4 37 55 2 36 12 21 2 58237002549 422381216260 7 0 0 2 39 15 21 2 132400202817 51241002958 10 10 26 2 42 27 31 2 11 20 25 2 43 21 32 2 12 11 57 2 44 19 31 2 024523342130 024618272140 15 0 0 2 47 88 71 2 024825382160 17 41 65 2 49 34 45 2 025023252180 19 50 67 2 51 48 46 2 20 2524536242 21 38 45 2 53 53 35 2 22 25 18 2 54 24 36 2 23 26 34 2 55 16 31 2 24 0 0 2 56 45 56 2 25 11 17 2 57 53 64 2 26 14 22 2 58 55 46 2 27 2593862212 28 43 58 2 60 68 64 2 290 34 2 61 22 25 2 2326215262300 27263212923125 32 16 23 2 64 56 67 2 Industrial Applicability The compounds according to the invention and the method of preparing thereof can be used in pharmaceutical production to make preparations with inhibitory effect on the enzyme acyl co-enzyme A and on cholesterol absorption in hypercholesterolemia.