CH654571A5 - ANTIATHEROSCLEROTIC, SUBSTITUTED UREA AND THIOURA COMPOUNDS. - Google Patents

Description

The present invention relates to substituted urine and thiourea compounds which are useful as pharmaceutical agents and some of which are new compounds. The compounds of the invention are anti-atherosclerotic agents capable of alleviating atherosclerosis by counteracting the formation or development of atheromatous lesions in the arterial wall of mammals. The invention also relates to the chemical synthesis of the compounds described therein. In addition, the invention relates to pharmaceutical compositions for the use of these compounds in the treatment of diseases in mammals.

A large number of urea and thiourea compounds are described in the literature, for example in J. Med. Chem. 18, 1024 (1975); Chem. 95.6758m (1981) and 91.74631g (1979); U.S. Patents 2,688,039.3 335 142.3 856 952.3 903130; and DE-OS 2 928 485. The compounds described in the literature are referred to as useful herbicides, plant growth regulators, bactericides, pesticides, fungicides, algazides, photographic sensitizers, anthelmintics, sympatholytics and antivirals. Those urea compounds which are described in DE-OS 2928485 are mentioned as being useful for inhibiting lipid absorption. However, there is no reference to disclose the tetrasubstituted urea and thiourea compounds of the present invention or their use in the treatment of atherosclerosis or hyperlipidemia.

Atherosclerosis is a form of arteriosclerosis, which is characterized by a build-up of fat in the arterial walls and a thickening of the arterial walls of medium and large arteries. The artery walls are softened and the elasticity and the effective internal size of the artery decrease. Atherosclerosis is the most common cause of ischemic heart disease and is of great medical importance since the occlusion of the medium and large arteries reduces the blood supply to the vital organs, such as the heart muscles and the brain. The after-effects of atherosclerosis include ischemic heart disease, heart failure, life-threatening arrhythmia, senility and stroke.

The fact that cholesterol is a major component of atherosclerotic lesions or deposits has been known for over 100 years. Various researchers have investigated the role of cholesterol in the formation and development of lesions, and more importantly, whether the formation of lesions can be prevented or the development of lesions arrested or reversed can be. It has now been shown [Adams et al., Atherosclerosis, 13, 429 (1974)] that atheromatous lesions contain a greater amount of esterified, as opposed to non-esterified, cholesterol than the surrounding artery wall, which is not affected by the disease. The intracellular esterification of cholesterol with fatty acids is catalyzed by the enzyme fatty acid acyl CoA: cholesterol acyl transferase or ACAT and the accumulation and deposition of the cholesteryl esters in the arterial wall is associated with an increased activity of the enzyme [Hashimoto and Dayton, Atherosclerosis, 28.447 (1977)] . In addition, cholesteryl esters are removed from cells at a slower rate than non-esterified cholesterol [Bondjers and Bjorkerud, Atherosclerosis, 15.273 (1972) 5 and 22.379 (1975)]. Inhibition of the ACTA enzyme would thus reduce the rate of cholesterol esterification, decrease the accumulation and deposition of the cholesteryl esters in the artery wall and prevent or inhibit the formation and development of athero-matrous lesions. The compounds according to the invention are very potent inhibitors of the ACAT enzyme. Therefore, these compounds are useful for controlling and reducing the cholesteryl ester content in mammalian artery walls and for reducing the accumulation and deposition of cholesterol in the mammalian artery walls. The compounds of the invention further inhibit the formation or development of atherosclerotic lesions in mammals.

The evidence that hyperlipidemia is one of the factors that play a role in coronary artery disease is extremely impressive. A major study conducted in Framingham, Massachusetts (Gordon and Verter, 1969) in over 5,000 people for more than 12 years found a correlation between high blood cholesterol levels and increased risk of heart attack. Even though the causes of coronary artery diseases are diverse, one of the extremely constant factors is the increased concentration of lipids in the blood plasma. It has been shown that a combined increase in cholesterol and triglycerides leads to the greatest risk 30 in coronary heart disease (Carlson and Bottiger, 1972). The majority of patients with ischemic heart disease or peripheral vascular disease have been found to have hyperlipoproteinemia, with very low-density and / or low-density lipoproteins playing a role ( Lewis et al., 1974).

The inventors have now found that certain members of this class of compounds can be used safely and effectively to reduce both serum lipids in warm-blooded animals 40. Such an effect on serum lipids is considered very useful for the treatment of atherosclerosis. For some time, it was believed that it was desirable to lower serum lipid levels and correct lipoprotein imbalance in mammals as a preventive measure against atherosclerosis. The compounds according to the invention do not work by blocking late stages of cholesterol biosynthesis and thus do not lead to the formation of accumulations of the intermediates, such as desmosterol, which are equally undesirable as cholesterol itself. Compounds according to the invention with the combination of therapeutically advantageous properties can be used safely Warmbloods are administered to treat hyperlipidemic and atherosclerotic conditions found in patients who have had a heart attack, 53 peripheral or cerebral vascular diseases or strokes, or who are at risk.

The compounds according to the invention have antiatherosclerotic activity. However, the invention is not intended to be limited to any particular mechanism of antiathero-60 sclerotic activity.

More specifically, the invention relates to certain new compounds which can be represented by the general formula I:

45

65

R

3 1

II

N - C

/ R1

N,

\

R.

(I)

654 571

4th

where X represents at least one substituent selected from hydrogen, Q-4-alkyl, C [-4-alkenyl, Cj-4-alkynyl, hydroxy, C] -4-alkoxy, phenoxy, mercapto, C1-4-alkylthio, Amino, Q - ^ - alkylamino, di- (Ci-4-alkyl) -amino, halogen, tri-halomethyl, Ci-4-alkanoyl, benzoyl, Ci-4-alkanamido, Ci-4-alkanesulfonyl, Ci-4- Alkanesulfinyl, benzenesulfonyl, toluenesulfonyl, nitro, cyano, carboxy, Ci-4-carboalkoxy, carbamoyl, sulfamoyl, methylenedioxy, phenyl, o-phenylene, tolyl, benzyl, halobenzyl, methylbenzyl and the group where Y is the formula ( II) has the meaning given and A u; B are independently selected from halogen. C, -alkoxy, Q-4-alkylthio, phenoxy, 4-chlorophenoxy and 4-nitrphenoxy, with a secondary amine of formula IV:

R

1

HN

(IV)

R

\ n

- C - N

10 where and R; have the meanings given in formula (II) for the preparation of an intermediate of the formula \

R,

\; H

Y

I!

A - C

where Y is selected from oxygen and sulfur; R | and R2 are identical or different and are independently selected from C4-i2-alkyl, C4-12-alkenyl, C4-I2-alkynyl, C4-i2 "cycloalkyl, C4-12-cycloalkylalkyl, C7-14-aralkyl and C7- Ci4-aralkyl, where an aromatic ring carries at least one substituent, selected from Ci-i0-alkyl, Ci-I0-alkoxy, phenoxy, benzyloxy, methylenedioxy, C] -4-alkylthio, phenyl, halogen, trihalomethyl, adamantyl, Q- 4-carboalkoxy and nitro; and R3 is selected from hydrogen, Ci-4-alkyl, Ci-4-alkenyl, Q - ^ - alinyl, benzyl, benzyl which carries at least one substituent Z, naphthyl, phenyl and phenyl, which carries at least one substituent Z, where Z is selected independently of X from the substituents from which X is selected and Rj and R2 are different from one another if R3 is hydrogen.

Preferred embodiments of the invention are the compounds in which Y is oxygen. Particularly preferred are those in which X is at least one C! -4-alkyl or halogen substituent and Rt and R2 are identical or different and are selected independently of one another from C4-i2-alkyl, C7-i4-aralkyl and substituted C7-14 aralkyl. Most preferred are those compounds in which X represents at least one methyl or chlorine substituent and Z represents hydrogen, methyl or chlorine.

The invention further relates to a process for the preparation of compounds of the formula II:

(VI)

■ R,

and the subsequent reaction of the intermediate product with an arylamine of the formula VII:

R-,

25th

NH

(VII)

where X and R3 have the meanings given for formula (II).

Another special process for the preparation of the compounds of the formula (II) comprises the reaction of a compound 30 of the formula V:

A - C - B

(V)

35 where Y has the meaning given for the formula (II) and A and B are selected independently of one another from halogen Q- ^ alkoxy, Q-j-alkylthio, phenoxy, 4-chlorophenoxy and 4-nitrophenoxy, with an arylamine of the formula VII:

40

R,:>

NH

(VII)

R-,

1

N - C - N

(II)

where X and Rj have the meanings 43 given for formula (II), for the preparation of an intermediate of formula VIII:

r3. Y

N - C - B

X-

(VIII)

in which X, Y, R [and R2 have the above meanings, R [

and R2 are different from each other and R3 is hydrogen. The process comprises the reaction of an aryl isocyanate or aryl thioisocyanate of the formula III with a second and the subsequent reaction of the intermediate product with the dear amine of the formula IV: a secondary amine of the formula IV:

N = C = Y

55

HN

HN

/ R1

(IV)

(III)

(IV)

where X, Y, Rj and R2 have the meanings given above.

A special process for the preparation of the compounds of formula (II) comprises the reaction of a compound of formula V:

11

- C

(V)

where R [and R; have the meanings 60 given in formula (II).

Finally, the invention relates to a pharmaceutical composition which is suitable for the treatment of atherosclerosis, for reducing the cholesterol ester content of the arterial wall, for inhibiting the development of athero-65 sclerotic lesions and / or for the treatment of hyperlipidemia in mammals which require such treatment. The pharmaceutical composition comprises an effective amount of a compound of formula I in which the

654 571

different symbols have the meanings given above.

Certain urea and thiourea compounds according to the present invention are prepared by reacting activated carboxylic acids of the formula V, such as phosgene, thiophosgene or phenylchloroformate, with secondary amines of the formula VII to produce an intermediate of the formula VIII, for example a disubstituted carbamoyl chloride. This intermediate product is in turn reacted with an arylamine of the formula IV. The intermediate product is preferably prepared in an appropriate solvent, such as tetrahydrofuran, toluene, xylene or the like, at temperatures from about room temperature to the boiling point of the solvent. The intermediate can be isolated by evaporation and purified by distillation if necessary. The intermediate can then be treated with the arylamine IV in an aprotic solvent such as dimethylacetamide in the presence of a base such as sodium hydride. at temperatures from about room temperature to the boiling point of the solvent used. An example of this process is the reaction of phosgene with N-benzyl-n-butylamine in toluene to produce the intermediate N-benzyl-N- (n-butyl) -carbamoyl chloride, which is then used with diphenylamine in NN-dimethylacetamide and in the presence of sodium hydride is reacted to obtain 1-benzyl-l- (n-butyl) -3,3-diphenylurea.

Other urea and thiourea compounds according to the present invention are prepared by reacting arylamines of the formula IV with activated carboxylic acids of the formula V, such as phosgene or thiophosgene, an intermediate of the formula VI, e.g. B. an arylcarbamoyl chloride. This intermediate product is then reacted with a secondary amine of the formula VII. The preparation of this intermediate is preferably carried out in an aprotic solvent, such as tetrahydrofuran, toluene or xylene, at temperatures from about room temperature to the boiling point of the solvent in the presence of a base, e.g. B. N, N-dimethylaniline. The intermediate is then reacted with the secondary amine VII, suitably in an aprotic solvent such as toluene, at temperatures from room temperature or below to the boiling point of the solvent. An example of this process is the reaction of phosgene with N-phenyl-3-chloroaniline to produce the intermediate N- (3-chlorophenyl) -N-phenylcarbamoyl chloride, which is then reacted with N-benzyl-n-butylamine to obtain l-benzyl-l- (n-butyl) -3- (3-chlorophenyl) -3-phenylurea.

The urea and thiourea compounds according to the invention which contain carboxy groups can be prepared by alkaline hydrolysis of the corresponding carboalkoxyurea and thiourea compounds which have been obtained by the synthesis processes described above. Correspondingly, those compounds which contain hydroxyl, mercapto or amino groups can be prepared by alkaline hydrolysis of the corresponding O-acetyl, S-acetyl and N-acetylurea and thiourea compounds. the latter also being obtained after the urea and thiourea syntheses described above. Alternatively, urea and thiourea compounds containing hydroxy groups can be prepared by cleaving the corresponding methoxy compounds using Lewis acids such as boron tribromide.

Certain substituted N-benzylanilines which are required as starting products for the synthesis of some of the new tetrasubstituted urea and thiourea compounds according to the present invention are not known from the prior art. These required N-benzylanilines are prepared by reacting various benzaldehydes with anilines to give anils. The anils are then reduced to produce the substituted N-benzylanilines. An example of such a synthesis involves the reaction of 2,4-dimethylbenzaldehyde with 1,4-dichloroaniline 5 to produce N- (2,4-dimethylbenzylidene) -2,4-dichloroanine, followed by reduction with sodium borohydride to produce N- (2,4-dimethylbenzyl) -2,4-dichloroaniline.

Many of the urea and thiourea compounds according to the present invention are made by reacting aryl isocyanates and aryl isothiocyanates with secondary amines. These reactions can be carried out in aprotic solvents such as hexane, diethyl ether, toluene, tetrahydrofuran and the like, at temperatures from room temperature or below to the boiling point of the solvent used. The urea and thiourea compounds are isolated by filtration or by evaporation of the solvent and can be purified by recrystallization, absorption chromatography or distillation under reduced pressure. An example of this process is the reaction of 2,4-dimethylphenyl isocyanate with di- (n-butyl) amine to produce 1,1-di- (n-butyl) -3- (2,4-dimethylphenyl) )-urea.

Many of the secondary amines required for the synthesis of the urea and thiourea compounds according to the invention can be produced by diborane reductions in the corresponding amides. An example of this reaction is the synthesis of N- (n-butyl) -2-chlorobenzylamine by diborane reduction of N- (n-butyl) -2-chlorobenzamide. Certain of the amides required for these reductions can be prepared by acylation of primary amines with carboxylic acids by methods known per se, e.g. B. by converting the carboxylic acid into the corresponding carboxylic acid chloride using thionyl chloride and then reacting the acid chloride with the primary amine in the presence of a base. One method that is particularly suitable for this transfer is the boron trifluoride etherate-catalyzed reaction of a carboxylic acid with a primary amine. An example of this conversion is the boron trifluoride etherate-catalyzed acylation of 2-chlorobenzylamine with 3-methoxyphenyl-acetic acid to produce N- (2-chlorobenzyl) -3-methoxy-phenylacetamide.

The urea and thiourea compounds according to the invention are obtained as crystalline solids or distillable liquids. They are characterized by sharp melting or boiling points and characteristic spectra. The compounds are considerably soluble in organic solvents, but are generally less soluble in water. Those compounds containing carboxylic acid groups can be converted to their alkali metal and alkaline earth metal salts by treatment with the appropriate metal hydroxides, and those compounds containing amino groups can be converted to their ammonium salts by treatment with organic acids or mineral acids. Both types of salt show increased water solubility. The properties and the usefulness of the compounds according to the invention are explained in more detail below in conjunction with the tables below.

The compounds of the invention have been tested for two types of biological activity related to their potential use as anti-atherosclerotic agents. The compounds were tested in vitro for their ability to inhibit the enzyme fatty acid acyl-Co A: cholesterol acyl transferase (ACAT) and in vivo for serum hypolipidemic activity, determined for their ability to inhibit lipid absorption in rats. The compounds were tested for their ability to inhibit ACAT according to the following procedure.

25th

30th

35

40

45

60

65,

654 571 6

Rat adrenaline glands are homogenized in a 0.2 M monobasic potassium phosphate buffer (pH 7.4) and centrifuged at 100 ° C for 15 min at 5 ° C.

The supernatant fluid, containing the microsomal fraction, serves as the source of the cholesterol esterifying enzyme, 5 fatty acyl CoA: cholesterol acyl transferase (ACAT). A mixture comprising 50 parts of the supernatant liquid obtained above, 10 parts of albumin (BSA) (50 mg / ml), 3 parts of the test compound (final concentration = 5.2 g / ml) and 500 parts of buffer are at 37 ° for 10 min C preincubated. After treatment 10 with 20 parts of Oleoyl CoA (I4C-0.4 Ci) the mixture is 10 min

Incubated compound at 37 ° C. A control mixture, with the test compound omitted, is prepared and treated in the same way. The lipids are extracted from the incubation mixture into an organic solvent and separated by means of thin layer chromatography. The cholesteryl ester fraction is counted in a scintillation counter. This procedure is a modification of that described by Hashimoto et al., Life Science, 12 (Part II), 1-12 (1973).

The results of this test on representative compounds of the invention are summarized in Table I.

lei

% Inhibition l-benzyl-l- (n-butyl) -3,3-diphenylurea 75.9

l-benzyl-l- (n-butyl) -3- (3-chlorophenyl) -3-phenylurea 72.3

l-benzyl-l- (n-butyl) -3- (2-naphthyl) -3-phenylurea 83.6

l-benzyl-l- (n-butyl) -3-benzyl-3-phenylurea 81.8

l-benzyl-l- (n-butyl) -3- (3-methylphenyl) -3-phenylurea 82.0

l-benzyl-l- (n-butyl) -3- (3-methoxyphenyl) -3-phenylurea 82.5

l-benzyl-l- (n-butyl) -3- (4-isopropoxyphenyl) -3-phenylurea 77.8

l-benzyl-l- (n-butyl) -3- (l-naphthyl) -3-phenylurea 76.3

l-benzyl-l- (n-butyl) -3- (2-naphthyl) -3- (3-chlorophenyl) urea 82.7

l-benzyl-l- (n-butyl) -3,3-di- (2-naphthyl) urea 93.2

1,3-dibenzyl-1,3-di (n-butyl) urea 95.4

l-benzyl-l- (n-butyl) -3- (3-methylphenyl) urea 92.3

l-benzyl-l- (n-butyl) -3- (3-trifluoromethylphenyl) urea 85.7

l-benzyl-l- (n-butyl) -3- (3,5-dichlorophenyl) urea 90.7

l-benzyl-l- (n-butyl) -3- (3,4-dichlorophenyl) urea 95.9

l-benzyl-l- (n-butyl) -3- (3-chlorophenyl) urea 88.6

l-benzyl-l- (n-butyl) -3- (2,4-dimethylphenyl) urea 91.3

l-benzyl-l- (n-butyl) -3- (2-methylphenyl) urea 78.8

l-benzyl-l- (n-butyl) -3- (4-methylphenyl) urea 78.0

l-Benzyl-l- (n-butyl) -3- (2,3-dimethylphenyl) urea 85.8

l-benzyl-l- (n-butyl) -3- (2,5-dimethylphenyl) urea 92.7

l-benzyl-l- (n-butyl) -3- (2,6-dimethylphenyl) urea 83.1

l-benzyl-l- (n-butyl) -3- (3,5-dimethylphenyl) urea 94.2

l-Benzyl-l- [l- (3-methoxyphenyl) -2-phenylethyl] -3- (2,4-dimethylphenyl) urea 86.4

l-Benzyl-l- [l- (4-benzyloxyphenyl) -2-phenylethyl] -3- (2,4-dimethylphenyl) urea 93.0

l-Benzyl-l- (1,2-diphenylethyl) -3- (2,4-dimethylphenyl) urea 95.0

l-benzyl-l- (n-butyl) -3- (3,4-dimethylphenyl) urea 87.1

l-Benzyl-l- [l- (3-methoxyphenyl) -2-phenylethyl] -3- (3-trifluoromethylphenyl) urea 88.1

l-benzyl-l- (n-butyl) -3- (3-chloro-2-methoxyphenyl) urea 84.5

l-Benzyl-l- (n-butyl) -3- (5-chloro-2-methoxyphenyl) urea 80.6

l-benzyl-l- (n-butyl) -3-phenyl thiourea 82.4

l- (n-Butyl) -l- (2-fluorobenzyl) -3- (2,4-dimethylphenyl) urea 82.6

l- (n-Butyl) -l- (4-fluorobenzyl) -3- (2,4-dimethylphenyl) urea 80.6

1- (n-Butyl) -1- (2-chlorobenzyl) -3- (2,4-dimethylphenyl) urea 95.5

1- (n-Butyl) -1- (2,6-dichlorobenzyl) -3- (2,4-dimethylphenyl) urea 74.5

1- (n-Butyl) -1- (4-bromobenzyl) -3- (2,4-dimethylphenyl) urea 81.0

l- (n-Butyl) -l- [4- (n-butyl) benzyl] -3- (2,4-dimethylphenyl) urea 94.4

1- (n-butyl) -1- (4-methylbenzyl) -3- (2,4-dimethylphenyl) urea 96.7

l- (n-Butyl) -l- (4-tert-butylbenzyl) -3- (2,4-dimethylphenyl) urea 96.4

1- (n-Butyl) -1- (4-chlorobenzyl) -3- (2,4-dimethylphenyl) urea 94.6

1- (n-butyl) -1- (4-methoxybenzyl) -3- (2,4-dimethylphenyl) urea 94.2

1- (n-Butyl) -1- (3,4-methylenedioxybenzyl) -3- (2,4-dimethylphenyi) urea 88.2

l- (n-Butyl) -l- (4-trifluoromethylbenzyl) -3- (2,4-dimethylphenyl) urea 93.3

1- (n-Butyl) -1- (4-phenylbenzyl) -3- (2,4-dimethylphenyl) urea 97.1

l- (n-Decyl) -l-benzyl-3- (2,4-dimethylphenyl) urea 96.1

l- (n-Butyl) -l- (2-phenylethyl) -3- (2,4-dimethylphenyl) urea 87.9

1- (n-Butyl) -1- [2- (4-fluorophenyl) ethyl] -3- (2,4-dimethylphenyl) urea 96.1

l- (n-Butyl) -l- [2- (4-chlorophenyl) ethyl] -3- (2,4-dimethylphenyl) urea 93.3

l- (n-Butyl) -l- [2- (3-methoxyphenyI) ethy] -3- (2,4-dimethylphenyI) urea 89.3

1- (n-Butyl) -1- (3-phenylpropyl) -3- (2,4-dimethylphenyl) urea 97.4

l- (n-butyl) -l-benzyl-3- (2,4,6-trimethylphenyl) urea 75.8

l- (n-Butyl) -l- [4- (n-hexyl) benzyl] -3- (2,4-dimethylphenyl) urea 93.8

l- (n-Butyl) -l- [2- (3-bromophenyl) ethyl]] - 3- (2,4-dimethylphenyl) urea 97.0

7,654,571

Table I (continued)

Compound% inhibition

[2- (3,4-Dimethoxyphenyl) ethyl] -1- (3-chloro-4-methylbenzyl) -3- (2,4-dimethylphenyl) urea 53.3

[2- (2-methylphenyl) ethyl] -1- (4-bromobenzyl) -3- (2,4-dimethylphenyl) urea 29.2

[2- (3-trifluoromethylphenyl) ethyl] -1- (2-chlorobenzyl) -3- (2,4-dimethylphenyl) urea 7.8

(2-Fluorobenzyl) -1- (2-methoxybenzyl) -3- (2,4-dimethylphenyl) urea 41.5

[2- (3,4-Dimethoxyphenyl) ethyl] -1- (4-fluorobenzyl) -3- (2,4-dimethylphenyl) urea 57.4

[2- (4-ethoxyphenyl) ethyl] -1- (2,4-dimethylbenzyl) -3- (2,4-dimethylphenyl) urea 34.9

[2- (3-methylphenyl) ethyl] -1- (3-nitrobenzyl) -3- (2,4-dimethylphenyl) urea 95.7

[2- (2,5-Dimethoxyphenyl) ethyl] -1- (3-chlorobenzyl) -3- (2,4-dimethylphenyl) urea 97.1

(n-Butyl) -l- (2-methyl-2,2-diphenyl) ethyl-3- (2,4-dimethylphenyl) urea 97.4

(n-Butyl) -l- (4-hexyloxybenzyl) -3- (2,4,6-trimethylphenyl) urea 97.1

(n-Butyi) -1- (4-heptoxyoxybenzyl) -3- (2,4,6-trimethylphenyl) urea 97.3

(n-Butyl) -l-benzyl-3- (4-trifluoroacetylamino-3,5-dichlorophenyl) urea 87.8

-Benzyl-l- (4-n-butylbenzyl) -3- (2,4-dimethylphenyl) urea 91.9

-Benzyl-l- (4-n-butylbenzyl) -3- (2,4,6-trimethylphenyl) urea 92.8

-Benzyl-l- (4-n-butylbenzyl) -3- (4-n-butylphenyl) urea 92.0

-Benzyl- l- (4-n-butylbenzyl) -3- (4-phenoxyphenyl) urea 93.5

- (n-Heptyl) -l- (4-n-butylbenzyl) -3- (2,4-dimethylphenyl) urea 94.8

- (n-Heptyl) -l- (4-n-butylbenzyl) -3- (2,4,5-trimethylphenyl) urea 95.3

-Benzyl-l- [2-phenyl-l- (4-benzyloxyphenyl) ethyl] -3- (2,4,5-trimethylphenyl) urea 93.7

- (n-Heptyl) -l- (4-butyloxybenzyl) -3- (2,4-dimethylphenyl) urea 94.6

- (n-Heptyl) -l- (4-butyloxybenzyl) -3- (2,4,5-trimethylphenyl) urea 95.6

-Benzyl-l- (4-butyloxybenzyl) -3- (2,4-dimethylphenyl) urea 91.7

-Benzyl-l- (4-butyloxybenzyl) -3- (2,4,5-trimethylphenyl) urea 95.8

-Benzyl-l- (4-n-butylbenzyl) -3- (2,4,5-trimethylphenyl) urea, 90.5

-Benzyl-l- [2-phenyl-l- (4-benzyloxyphenyl) ethyl] -3- (2,4,6-trimethylphenyl) urea 90.0

- (n-Heptyl) -l- (4-n-butoxybenzyl) -3- (2,4,6-trichlorophenyl) urea 90.0

- (n-Heptyl) - (4-n-butoxybenzyl) -3- (2,4-dichlorophenyl) urea 79.9

- (n-Heptyl) - (4-n-butoxybenzyl) -3- (2-trifluoromethyl) -4-chlorophenyl) urea 89.4

-Benzyl-l- (4-n-butoxybenzyl) -3- (2,4,6-trichlorophenyl) urea 95.2

-Benzyl-l- (4-n-butoxybenzyl) -3- (2,4-dichlorophenyl) urea 80.0

-Benzyl-l- (4-n-butoxybenzyl) -3- (2-trifluoromethyl-4-chlorophenyl) urea 85.0

- (n-Heptyl) -l- (4-n-butoxybenzyl) -3- (3-trifluoromethylphenyl) urea 82.4

- (n-Benzyl) -l- (4-n-butoxybenzyl) -3- (3-trifluoromethylphenyl) urea 87.0

- (n-heptyl) -l- (4-n-butylbenzyl) -3- (2,4-dichlorophenyl) urea 80.0

- (n-Heptyl) -l- (4-n-butylbenzyl) -3- (2-trifluoromethyl-4-chlorophenyl) urea 90.0

- (n-Heptyl) -l- (4-n-butylbenzyl) -3- (2,4,6-trichiorphenyl) urea 90.0

- (n-Heptyl) -l- (4-n-butylbenzyl) -3- (3-trifluoromethylphenyl) urea 85.0

- (n-Heptyl) -l- (4-n-butylbenzyl) -3- (2,4,5-trichlorophenyl) urea 46.5

-Benzyl-l- (4-n-butylbenzyl) -3- (2-methyl-4-chlorophenyl) urea 94.3

- (n-Heptyl) -l- (4-n-butoxybenzyl) -3- (2,4-difluorophenyl) urea 82.7

- (n-Heptyl) -l- (4-n-butoxybenzyl) -3- (2-methyl-4-chlorophenyl) urea 91.7 ~

- (n-Heptyl) -l- (2-furyl) -3- (2,4,5-trimethylphenyl) urea 93.8

- (n-Heptyl (-l- (2-furyl) -3- (2,4,6-trichlorophenyl) urea 96.1

- (n-Heptyl) -l- (4-n-butylbenzyl) -3- (2-methyl-4-chlorophenyl) urea 92.5

- (n-Heptyl) -l- (4-n-butylbenzyl) -3- (2,4-difluorophenyl) urea 90.0

- (n-Heptyl) -l- (4-n-butylbenzyl) -3- (4-carboethoxyphenyl) urea 92.4

- (n-Heptyl) -l- (4-n-butylbenzyl) -3- (2-methylphenyl) urea 97.4

- (n-Heptyl) -l- (4-n-butylbenzyl) -3- (3-methylphenyl) urea 93.8

- (n-Heptyl) -l- (4-n-butylbenzyl) -3- (4-carboxyphenyl) urea 61.8

- (n-Heptyl) -l- (2-phenylethyl) -3- (2-methyl-4-chlorophenyl) urea 93.8

- (n-Heptyl) -l- (2-phenylethyl) -3- (2,4,5-trichlorophenyl) urea 77.3

- (n-Heptyl) -l- (2-phenylethyl) -3- (2-trifluoromethyl-4-chlorophenyl) urea 88.3

- (n-Heptyl) -l- (2-phenylethyl) -3- (2,4-dimethylphenyl) urea 95.7

- (n-Heptyl) -l- (2-phenylethyl) -3- (2,4-dichlorophenyl) urea 91.8

- (n-Heptyl) -l- (2-phenylethyl) -3- (2,4-difluorophenyl) urea 94.1

- (n-Heptyl) -l- (2-phenylethyl) -3- (3-trifluoromethylphenyl) urea 88.4

-Benzyl-l- [2-phenyl-l- (4-benzyloxyphenyl) ethyl] -3- (2,4,6-trichlorophenyl) urea 95.0

- (4-n-Pentylbenzyl) -l- (4-n-pentyioxybenzyl) -3- (2,4,6-trichlorophenyl) urea 95.5

- (4-n-Pentylbenzyl) -l- (4-n-pentyloxybenzyl) -3- (2,4-dichlorophenyl) urea 85.0

- (4-n-Pentylbenzyl) -l- (4-n-pentyloxybenzyl) -3- (2,4,5-trichlorophenyl) urea 80.0

- (4-n-Pentylbenzyl) -l- (4-n-pentyloxybenzyl) -3- (2-trifluoromethyl-4-chlorophenyl) urea 81.0

- (4-n-Pentylbenzyl) -l- (4-n-pentyloxybenzyl) -3- (3-trifluoromethylphenyl) urea 85.0

- (4-n-Pentylbenzyl) -l- (4-n-pentyloxybenzyl) -3- (2,4-difluorophenyl) urea 90.0

- (4-n-Pentylbenzyl) -l- (4-n-pentyloxybenzyl) -3- (2-methyl-4-chlorophenyl) urea 91.0

- (4-Chlorobenzyl) -1 - (1 -naphthylmethyl) -3- (2,4,6-trichlorophenyl) urea 77.0

654 571

connection

8th

Table I (continued)

9c inhibition l- (4-chlorobenzyl) -l- (l-naphthylmethyl) -3- (2-methyl-4-chlorophenyl) urea 94.0

l- (4-chlorobenzyl) -l- (l-naphthyimethyl) -3- (2,4-difIuorphenyI) urea 84.0

1- (4-chlorobenzyl) -1- (1-naphthylmethyl) -3- (3-trifluoromethylphenyl) urea 80.0

1- (4-chlorobenzyl) -1- (1-naphthylmethyl) -3- (2,4,5-trichlorophenyl) urea 86.0

l-Benzyl-l- [2-phenyl-l- (4-benzyloxvphenyl) ethyl] -3- (2,4,5-trichlorophenyl) urea 95.0

l-Benzyl-l- (4-n-butyloxybenzyl) -3- (2,4,5-trichlorophenyl) urea 89.0

l-Benzyl-l- [2-phenyl-l- (4-benzyloxyphenyl) ethyl] -3- (2,4-difluorophenyl) urea 70.0

l-benzyl-1- (4-n-butoxybenzyl) -3- (2,4-difluorophenyl) urea 88.0

l-Benzyl-l- [2-phenyl-l- (4-benzyloxyphenyl) ethyl] -3- (2,4-difluorophenyl) urea 91.0

l-Benzyl-l- [2-phenyl-l- (4-benzyloxyphenyl) ethyl] -3- (2-trifluoromethyl-4-chlorophenyl) urea 92.0

l-Benzyl-l- [2-phenyl-l- (4-benzyloxyphenyl) ethylj-3- (3-trifluoromethylphenyl) urea 74.0

l-Benzyl-l- [2-phenyl-1- (4-benzyloxyphenyl) ethyl] -3- (2-methyl-4-chlorophenyl) urea 89.3

1- (4-chlorobenzyl) -1- (1-naphthylmethyl) -3- (2,4-dichlorophenyl) urea 92.0

1- (4-chlorobenzyl) -1- (1-naphthylmethyl) -3- (2-trifluoromethyl-4-chlorophenyl) urea 83.0

Inhibition of cholesterol absorption was determined by feeding male Sprague-Dawley rats weighing 150-170 g with a 1% cholesterol: 0.5% cholic acid diet for 2 weeks. The food also contained the compounds to be examined at a dose of 0.03% of the diet. Control rats were treated with the n5

fed the same diet with no compound added. At the end of the test, the rats were killed by decapitation. The blood was collected, centrifuged at 1.5 kg times gravitational acceleration for 10 min at 4 ° C., and the serum was then analyzed enzymatically for cholesterol and triglycerides according to the procedure of P. Trinder, 30 Analyst, 77, 321 (1952) on a centrifichem 400 analyzers.

Table II

connection

The liver was removed, a 0.4 g sample was taken from the center of the large flap and the sample was subjected to saponification using 25 cc saturated potassium hydroxide in ethanol. The resulting neutral sterols were extracted with petroleum ether and the extract was analyzed for cholesterol. The effectiveness of the invention in inhibiting cholesterol absorption was measured by reducing either the serum cholesterol or the liver cholesterol, relative to the values obtained for control rats.

The results of this test for typical compounds according to the invention are shown in Table II.

result

■ Benzyl-l- (n-butyl) -3- (3-methoxyphenyl) -3-phenylurea active

Benzyl-l- (n-butyl) -3- (2,4-dimethylphenyl) urea active

Benzyl-l- (n-butyl) -3- (2,6-dimethylphenyl) urea active

Benzyl-l- (n-butyl) -3- (3,5-dimethylphenyl) urea active

■ Benzyl-l- (1,2-diphenylethyl) -3- (2,4-dimethylphenyI) urea active

(2-Fluorobenzyl) ~ l- (2-methoxybenzyl) -3- (2,4-dimethylphenyl) urea active

(n-Butyl) -l- (4-hexyloxybenzyl) -3- (2,4,6-trimethylphenyl) urea active

(n-Butyl) -l- (4-heptyloxybenzyl) -3- (2,4,6-trimethylphenyl) urea active

• Benzyl-1- (4-n-butylbenzyl) -3- (2,4-dimethylphenyl) urea active

• Benzyl-1- (4-n-butylbenzyl) -3- (2,4,6-trimethylphenyl) urea active

■ Benzyl-1- (4-n-butylbenzyl) -3- (4-n-butylphenyl) urea active

(n-HeptyI) -l- (4-n-butylbenzyI) -3- (2,4-dimethylphenyl) urea active

(n-Heptyl) -l- (4-n-butylbenzyl) -3- (2,4,5-trimethylphenyl) urea active

(N-heptyl) -1- (4-butyloxybenzyl) -3- (2,4-dimethylphenyl) urea active

• (n-Heptyl) -l- (4-butyloxybenzyl) -3- (2,4,5-trimethylphenyl) urea active

■ Benzyl-1- (4-butyloxybenzyl) -3- (2,4-dimethylphenyl) urea active

■ Benzyl-1- (4-butyloxybenzyl) -3- (2,4,5-trimethylphenyl) urea active

• Benzyl-1- (4-n-butylbenzyl) -3- (2,4,5-trimethylphenyl) urea active

• Benzyl-l- [2-phenyl-l- (4-benzyloxyphenyl) ethyl] -3- (2,4,6-trimethylphenyl) urea active

- (n-Heptyl) -l- (4-n-butoxybenzyl) -3- (2,4,6-trichlorophenyl) urea active

(n-Heptyl) - (4-n-butoxybenzyl) -3- (2,4-dichlorophenyl) urea active

• (n-Heptyl) - (4-n-butoxybenzyl) -3- (2-trifluoromethyl-4-chlorophenyl) urea active

• Benzyl-1- (4-n-butoxybenzyl) -3- (2,4,6-trichlorophenyl) urea active

-Benzyl-l- (4-n-butoxybenzyl) -3- (2,4-dichlorophenyl) urea active

-Benzyl-l- (4-n-butoxybenzyl) -3- (2-trifluoromethy! -4-chlorophenyl) urea active

- (n-Heptyl) -l- (4-n-butoxybenzyl) -3- (3-trifluoromethylphenyl) urea active

• (n-Heptyl) -l- (4-n-butylbenzyl) -3- (2,4-dichlorophenyl) urea active

- (n-Heptyl) -l- (4-n-butylbenzyl) -3- (2-trifluoromethyl-4-chlorophenyl) urea active

• (n-Heptyl) -I- (4-n-butylbenzyl) -3- (2,4,6-trichlorophenyl) urea active

Benzyl-1- (4-n-butylbenzyl) -3- (2-methyl-4-chlorophenyl) urea active

- (n-Heptyl) -l- (4-n-butoxybenzyl) -3- (2,4-difluorophenyl) urea active

(n-Heptyl) -l- (4-n-butoxybenzyl) -3- (2-methyl-4-chlorophenyl) urea active

(n-Heptyl) -l- (2-furyl) -3- (2,4,5-trimethyIphenyI) urea active

654 571

Table II (continued)

Connection result

Mn-heptyl) -l- (2-furyl) -3- (2,4,6-trichlorophenyl) urea active l- (n-heptyl) -l- (4-n-butylbenzyl) -3- (2- methyl-4-chlorophenyl) urea active l- (n-heptyl) -l- (4-n-butylbenzyl) -3- (2,4-difluorophenyl) -urea active l- (n-heptyl) -l- ( 4-n-butylbenzyl) -3- (4-carboethoxyphenyl) urea active l- (n-heptyl) -l- (4-n-butylbenzyl) -3- (2-methylphenyl) urea active l- (n- Heptyl) -l- (4-n-butylbenzyl) -3- (3-methylphenyl) urea active l- (n-heptyl) -l- (2-phenylethyl) -3- (2-methyl-4-chlorophenyl) -urea active l- (n-heptyl) -l- (2-phenylethyl) -3- (2-trifluoromethyl-4-chlorophenyl) -urea active

Hn-heptyl) -l- (2-phenylethyl) -3- (2,4-dimethylphenyl) urea active l- (n-heptyl) -l- (2-phenylethyl) -3- (2,4-dichlorophenyl) -urea active l- (n-heptyl) -l- (2-phenylethyl) -3- (2,4-difluorophenyl) -urea active l- (n-heptyl) -l- (2-phenylethyl) -3- ( 3-trifluoromethylphenyl) urea active l-benzyl-l- [2-phenyl-l- (4-benzyloxyphenyl) ethyl] -3- (2,4,6-trichlorophenyl) urea active l- (4-n- Pentylbenzyl) -l- (4-n-pentyloxybenzyl) -3- (2,4,6-trichlorophenyl) urea active l- (4-n-pentylbenzyl) -l- (4-n-pentyloxybenzyl) -3- ( 2,4-dichlorophenyl) urea active l- (4-n-pentylbenzyl) -l- (4-n-pentyloxybenzyl) -3- (2,4,5-trichlorophenyl) urea active l- (4-n- Pentylbenzyl) -l- (4-n-pentyloxybenzyl) -3- (2,4-difluorophenyl) urea active l- (4-n-pentylbenzyl) -l- (4-n-pentyloxybenzyl) -3- (2- methyl-4-chlorophenyl) urea active l- (4-chlorobenzyl) -l- (l-naphthylmethyl) -3- (2,4,6-trichlorophenyl) -urea active l- (4-chlorobenzyl) -l- ( l-naphthylmethyl) -3- (2-methyl-4-chlorophenyl) urea active l- (4-chlorobenzyl) -l- (l-naphthylmethyl) -3- (2,4-difluorophenyl) urea active l- (4-chlorobenzyl) -l- (l-naphthylmethyl) -3- (3-trifluoromethylphenyl) -urea active l- (4-chlorobenzyl) -l- (l-naphthylmethyl) ) -3- (2,4,5-trichlorophenyl) urea active l-benzyl-l- (4-n-butyloxybenzyl) -3- (2,4,5-trichlorophenyl) urea active l-benzyl-l- [2-phenyl-l- (4-benzyloxyphenyl) ethyl] -3- (2,4-difluorophenyl) urea active l-benzyl-l- (4-n-butoxybenzyl) -3- (2,4-difluorophenyl ) -urea active l-benzyl-l- [2-phenyl-l- (4-benzyloxyphenyl) ethyl] -3- (2-trifluoromethyl-4-chlorophenyl) -urea active l-benzyl-l- [2-phenyl -l- (4-benzyloxyphenyl) ethyl] -3- (2-methyl-4-chlorophenyl) urea active l- (4-chlorobenzyl) -l- (l-naphthylmethyl) -3- (2,4-dichlorophenyl ) -Urea active

All test results reported in Tables I and II. Radioactivity in the liver and adrenaline glands is the result of tests actually performed. 35 is determined by saponification and extraction with petroleum ether

The inhibition of cholesterol absorption was also increased and counted using scintillation techniques. The total chole

by male Sprague-Dawley rats with sterol in the liver and adrenal glands was determined weighing 150 to 170 g with a 1% cholesterol ^. 5% by the colorimetric method of A. Zlatkis et al., J.

Cholic acid diet fed 2 weeks. The diet included those from Lab. Clin. Med., 41,486 (1953), for saponified tissues extracted with organic investigating compounds with doses between 0.01 and 40 solvents, produced according to the method

0.1% of the diet. After the rats ride the test diet for 9 days, P. Trinder, Analyst, 77.321 (1952). Serum cholesterol, each rat was fed using a and triglycerides were determined enzymatically after the

Gavage a sonicated mixture of [4-I4C] cholesterol from C.C. Allainetal., Clin. Chem. 20,470 (1974)

(6 Ci), 0.2 ml triolein, 10 mg cholic acid, 20 mg cholesterol and a Centrifichem 400 analyzer. 14C cholesterol in serum

2 mg of the test compound in 0.8 ml of 10% non-fat dry 43 was determined by direct scintillation counting.

given milk. During the remaining 5 days during which the effect of the test compound on the cholesterol absorber-the rats on the 1% cholesterol ^), 5% cholic acid plus test is determined by:

Binding diet were maintained, the excrement was- (1) increase in excreted, 14C-neutral sterol;

collected every 24 hours. Faecal 14C-new- (2) reduction in excreted 14C acid sterol;

Central sterols were extracted with petroleum ether from the saponified excreta 50 (3) reduction of 14C-cholesterol or 14C-cholesteryl-

extracted using the procedure of S.M. esters in the liver;

Grundy et al., J. Lipid Res., 6,397 (1965), and in one (4) reduction in 14C-cholesterol or 14C-cholesteryl-

Scintillation counter counted. Acid sterols (bile acids) were esters in the serum.

which is extracted by acidifying the saponified excrement and a compound is used to inhibit the

Extraction with chloroform / methanol (2: 1) and counting the 55 sterol absorption are considered active if they are at least that

Chloroform phasc in a scintillation counter. The overall first two criteria are met. The results of this test on traction of the radioactivity (98 to 100%) from the saponified typical compounds of the invention are shown in Table III.

Excrement is made using this procedure. set.

Table III

Compound Result l-benzyl-l- (n-butyl) -3- (2,4-dimethylphenyl) urea active l.l-dibenzyl-3- (2,4-dimethylphenyl) urea active

The test results shown in Table III are the result of tests actually performed.

When the compounds according to the invention are used for the purposes mentioned above, they can be combined with one or more pharmaceutically acceptable carriers, i. H. with solvents, diluents and the like.

654 571

10th

NEN orally administered, for example in the form of tablets, capsules, dispersible powders, granules, suspensions, for example, containing about 0.5 to 5% of a suspending agent, syrups, for example, containing about 10 to 50% sugar, and elixirs, for example contain about 20 to 50% ethanol and the like. The agents can also be administered parenterally in the form of sterile, injectable solutions or suspensions which contain about 0.5 to 5% of a suspending agent in an isotonic medium. These pharmaceutical preparations can contain, for example, 0.5 to about 90% of the active ingredient in combination with the carrier, but generally between 5 and 60% by weight of the active ingredient.

The antiatherosclerotic effective dose of the active ingredient used can vary, depending on the compound used, the mode of administration and the severity of the disease situation to be treated. However, generally satisfactory results are obtained when the compounds according to the invention are administered at a daily dose of from about 2 mg to about 500 mg / kg of body weight, preferably given in divided doses two to four times a day or in the form of a delayed release. For the largest mammals, the total daily dose is about 100 to about 5000 mg, preferably about 100 to 2000 mg. Dosage forms suitable for internal use comprise about 25 to 500 mg of the active ingredient in intimate admixture with a solid or liquid pharmaceutically acceptable carrier. This dose instruction can be set according to the optimal therapeutic response. For example, several divided doses can be administered daily or the dose can be reduced accordingly as the therapeutic situation progresses. A distinct, practical advantage is that these agents can be administered orally, as well as intravenously, intramuscularly or subcutaneously, if necessary. Solid carriers include starch, lactose, dicalcium phosphate, microcrystalline cellulose, sucrose and kaolin, while liquid carriers include sterile water, polyethylene glycol, nonionic surfactants and edible oils such as corn, peanut and sesame oil. These carriers are suitable depending on the nature of the active ingredient and the particular form of administration desired. Excipients, such as are usually used in the production of pharmaceutical compositions, can advantageously be added, for example flavors, colors, preservatives and antioxidants, e.g. B. Vitamin E, ascorbic acid, BHT and BHA.

Preferred pharmaceutical compositions from the standpoint of ease of manufacture and administration are solid compositions, particularly tablets and hard-filled or liquid-filled capsules. Oral administration of the compounds is preferred.

The active compounds can also be administered parenterally or intraperitoneally. Solutions or suspensions of the active substances as free base or pharmacologically acceptable salts can be prepared in water which is appropriately mixed with a surfactant such as hydroxypropyl cellulose. Dispersions can also be made in glycerin, liquid polyethylene glycols, and mixtures thereof in oils. Under normal conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.

Pharmaceutical forms suitable for use by injection include sterile, aqueous solutions or dispersions and sterile powders for the external manufacture of sterile, injectable solutions or dispersions. In all cases, the form must be sterile and liquid to such an extent that easy injectability is guaranteed. The shape must be stable under the conditions of manufacture and storage and must be protected against the contaminating effects of microorganisms such as bacteria and fungi. The carrier can be a solvent or a dispersion medium, which can be, for example, water, ethanol, polyol (such as glycerol, propylene glycol and liquid polyethylene glycol). contains suitable mixtures thereof and vegetable oils.

The production of representative compounds is explained in more detail below with the aid of examples.

example 1

l-Benzyl-l- (n-butyl) -3,3-diphenylurea A solution of 20.0 g of phosgene in 100 ml of toluene is stirred at 0 ° C 20, while a solution of 32.6 g of N-benzyl-n -butylamine in 50 ml of toluene is added over 15 min. The mixture is filtered and the filtrate evaporated. The residue is subjected to evaporation distillation at 105 ° C under reduced pressure (250 to 350 microns) to give N-benzyl-N- (n-butyl) carbamyl chloride as a colorless liquid.

A solution of 3.89 g of diphenylamine in 25 ml of dimethylacetamide is stirred for 1 hour in a stirred mixture of 5.19 g of N-benzyl-N- (n-butyl) carbamyl chloride, 0.685 g of sodium hydride and 65 ml of dimethylacetamide under a nitrogen atmosphere added at 45 30 to 50 ° C. The mixture is stirred at 50 ° C. for 2 h and then poured into water. The mixture is extracted with methylene chloride and the extract is evaporated. The residue is purified by chromatography using silica gel as the desorbent and Ace-35 ton / hexane as the eluent. After evaporation of the eluent, the residue is evaporated at 165 ° C. under reduced pressure (150 microns), giving l-benzyl-l- (n-butyl) -3,3-diphenylurea as a viscous, clear, colorless liquid.

25th

40

Example 2

l-Benzyl-l- (n-butyl) -3- (3-chlorophenyl) -3-phenylurea A solution of 5.09 g of N-phenyl-3-chloroaniline in 20 ml of toluene becomes a solution of 4.70 g Phosgene and 3.64 g of N, N-dimethylaniline added in 55 ml of toluene and the mixture warmed to 43 40 ° C. The mixture is then stirred, cooling to room temperature over 45 minutes. The mixture is extracted with water and the organic layer is separated off and evaporated to about half its volume. 100 ml of toluene are added to this solution, followed by 9.80 g of N-50 benzyl-n-butylamine. The resulting mixture is stirred under reflux for 30 min and then washed with water, 1N hydrochloric acid and saturated sodium bicarbonate solution. The organic layer is separated off, dried over sodium sulfate, decolorized using activated carbon and evaporated. The residue is evaporated at 185 to 190 ° C under reduced pressure (105 microns), using l-benzyl-l- (n-butyl) -3- (3-chlorophenyl) -3-phenylurea as a viscous, pale yellow Receives liquid.

The compounds listed in Table IV were obtained from the appropriate amines using phosgene or thiophosgene using the methods of Examples 1 and 2.

Table IV

Example connection

Mp

3rd

4th

l, 3-DibenzyI-l- (l-n-butyl) -3-phenylurea l-benzyl-I- (n-butyl) -3- (2-naphthyl) -3-pheny! urea yellow oil orange oil

11

654 571

Table IV (continued)

Example connection

Mp

D

6

7

8th

9

10th

11

12

13

14

15

16

17th

18th

19th

20th

21st

22

23

24th

25th

26

27th

Benzyl-benzyl-benzyl-benzyl-benzyl-benzyl-benzyl-benzyl-benzyl-benzyl-1-benzyl 1-benzyl 1-benzvl-

1-

Benzyl Benzyl Benzyl Benzyl Benzyl Benzyl Benzyl -Benzyl -Benzyl l- (n-butyl) -3- (3-methylphenyl) -urea l- (n-butyl) -3- (4-isopropylphenyl) -3-phenylurea l- ( n-butyl) -3- (3-methoxyphenyl) -3-phenylurea l- (n-butyl) -3- (3-chlorophenyl) -3- (2-naphthyl) urea l- (n-butyl) -3 - (l-naphthyl) -3-phenylurea l- (n-butyl) -3-benzyl-3- (4-chlorophenyl) urea l- (n-butyl) -3-benzyl-3- (2.4-dimethylphenyl) urea l- (n-butyl) -3-benzyl-3- (2,4-dichlorophenyl) urea l- (n-butyl) -3- (3-nitrobenzyl) -3- (3,5-dimethoxyphenyl) -urea l- (n-butyl) -3- (2,4-dimethylbenzyl) -3- (2,4-diphenyl) -urea l- (n-butyl) -3- (2.4-dichlorobenzyl) -3- ( 2,4-dichlorophenyl) urea l- (n-butyl) -3- (2-chlorobenzyl) -3- (2-chlorophenyl) urea l- (n-butyl) -3- (4-methylphenyl) -3 - (4-methylbenzyl) urea l- (n-butyl) -3- (2,4-dimethylbenzyl) -3- (2,4-dichlorophenyl) urea l- (n-butyl) -3- (2, 4-dichlorobenzyl) -3- (2,4-dimethylphenyl) urea l- (n-butyl) -3- (3-chloro-4-methylbenzyl) -3- (4-methylphenyl) urea l- (n- butyl) -3- (2,4-dimet hylbenzyl) -3-phenylurea l- (n-butyl) -3- [3,5-di- (trifluoromethyl) benzyl] -3-phenylurea l- (n-butyl) -3- (3-aminobenzyl) -3 - (3,5-dimethoxyphenyl) urea picrate l- (n-butyl) -3-benzyl-3- (3-aminophenyl) urea l- (n-butyl) -3-benzyl-3- (2,4, 6-trimethylphenyl) urea l- (n-butyl) -3-benzyl-3- (3-nitrophenyl) urea l- (n-butyl) -3-benzyl-3- (3-acetamidophenyl) urea

01

amber. Oil amber. Oil yellow oil amber. oil

oil

oil

oil

oil

oil

oil

oil

oil

oil

oil

oil

oil

oil

156-158 ° C 96-98 ° C 63-69 ° C yellow oil oil

Preparation of the starting products N- (2,4-dimethylbenzylidene) -2,4-dichloroaniline A mixture of 26.8 g of 2,4-dimethylbenzaldehyde, 32.4 g of 2,4-dichloroaniline, 0.20 g of pT oluenesulfonic acid and 150 ml of T oluol is refluxed using a Dean Stark drain

Scheiders stirred. Evaporation of the mixture gives a solid which is recrystallized from ethanol. This gives N- (2,4-dimethylbenzylidene) -2,4-dichloroaniline, mp. 102 to 106 °.

Anilines prepared by the procedure of the example are listed in Table V.

Table V

Connection Fp.

N-benzylidene-2,4,6-trimethylaniline

N-benzylidene-2,4-dichloroaniline

N- (4-methylbenzylidene) -3-chloro-4-methylaniline

N- (2,4-dimethylbenzylidene) -2,4-dimethylaniIin

N- (2,4-dichlorobenzylidene) -2,4-dimethylaniline

N- (3-nitrobenzylidene) -3,5-dimethoxyaniline

N-benzylidene-4-chloroaniline

N-benzylidene-2,4-dimethylaniline

N- (2,4-dichlorobenzylidene) -2,4-dichloroaniline

N- (2-chlorobenzylidene) -2-chloroaniline

N- (4-methylbenzylidene) -4-methylaniiin

N-benzylidene-3,5-di (trifluoromethyl) aniline

N- (4-Benzyloxybenzylidene) -4-carboethoxyaniline

N-benzylidene-3-nitroaniIin

N- (2,4-Dimethylbenzyl) -2,4-dichloroaniline A mixture of 13.9gN- (2,4-dimethylbenzylidene) -2,4-di-chloroaniline, 1.89 g of sodium borohydride and 150 ml of ethanol is stirred 1 h under reflux, let it cool and pour it into yellow oil

60-63 °

86-89 °

118-121 °

105-107 °

113-116 °

60-62 °

oil

134-139 °

111-117 °

90-93 °

yellow oil

140-142 °

69-72 °

Water. Recrystallization from ethanol gives N- (2,4-dimethyl-benzyl) -2,4-dichloroaniline, mp. 88 to 90 °.

55 Anilines prepared by the procedure of the example are listed in Table VI.

Table VI

Connection Fp. (°)

N-Benzy! -2,4,6-trimethylaniline oil

N-benzyl-2,4-dichloroaniline oil

N- (4-methylbenzyl) -3-chloro-4-methvlanilin oil

N- (2,4-dimethylbenzyl) -2,4-dimethylaniline 72-74

N- (2,4-dichlorobenzyl) -2,4-dimethylaniline 70-72

N- (3-nitrobenzyl) -3,5-dimethoxyaniline amber. oil

N-benzyl-4-chloroaniline 48-49

N-benzyl-2,4-dimethylaniline 28-33

N- (2,4-dichlorobenzyl) -2,4-dichloroaniline 84-86

654 571 12

Table VI (continued)

Connection Fp. (°)

N- (2-chlorobenzyl) -2-chloroaniline 41-44

N- (4-methylbenzyl) -4-methylaniline 50-54

N-benzyl-3,5-di (trifluoromethyl) aniline oil

N- (4-Benzyloxybenzyl) -4-carboethoxyaniline 147-150

N-benzyl-3-nitroaniline 106-108

Example 28

l-Benzyl-l- (n-butyl) -3- (2,4-dimethylphenyl) urea A solution of 4.89 g of 2,4-dimethylphenyl isocyanate in 100 ml of hexane becomes a solution of 4.41 g of N- Benzyl-n-butylamine was added to 150 ml of hexane, the solution was stirred at room temperature for 2 h and then evaporated. The remaining solid

10th

is recrystallized from pentane. and l-benzyl-l- (n-butyl) -3- (2,4-dimethylphenyl) urea is obtained, mp. 70 to 12 °.

The compounds listed in Table VII are prepared from the appropriate aryl isocyanates or aryl isothiocvanates and secondary amines by the process of Example 28.

Table VII

Example connection

FP. n

29 l-Benzyl-l- (n-butyl) -3- (2-methylphenyl) urea 48-53

30 l-benzyl-l- (n-butyl) -3- (3-methylphenyl) urea 91-92

31 l-benzyl-l- (n-butyl) -3- (4-methylphenyl) urea 102-103

32 l-benzyl-l- (n-butyl) -3- (2,3-dimethylphenyl) urea 77-78

33 l-Benzyl-l- (n-butyl) -3- (2,5-dimethylphenyl) urea 87-89

34 l-Benzyl-l- (n-butyl) -3- (2-6-dimethylphenyl) urea 125-126

35 l-Benzyl-l- (n-butyl) -3- (3,4-dimethylphenyl) urea 94-95

36 l-Benzyl-1- (n-butyl) -3- (3,5-dimethylphenyl) urea 108-109

37 l-benzyl-l- (n-butyl) -3- (2,4,6-trimethylphenyl) urea 141-144

38 l-benzyl-l- (n-butyl) -3- (3,4,5-trimethoxyphenyl) urea 144-145

39 l-benzyl-l- (n-butyl) -3- (3,4-dichlorophenyl) urea 102-105

40 l-Benzyl-1- (n-butyl) -3- (3,5-dichlorophenyl) urea 100-103

41 l-Benzyl-1- (n-butyl) -3- (3-trifluoromethylphenyl) urea 86-87

42 l-Benzyl-l- (n-butyl) -3- (3-chloro-2-methoxyxphenyl) urea 52-54

43 l-benzyl-l- (n-butyl) -3- (5-chloro-4-methoxyphenyl) urea 61-63

44 l-Benzyl-l- (n-butyl) -3- (3-chloro-4-methylphenyl) urea yellow oil

45 l-Benzyl-l- (1,2-diphenylethyl) -3- (2,4-dimethylphenyl) urea 157-158

46 l-Benzyl-l- [l- (3-methoxyphenyl) -2-phenyl-ethyl] -3- (2,4-dimethylphenyl) urea 124-126

47 l-Benzyl-1-- [l- (4-benzyloxyphenyl) -2-phenyl] -3- (2,4-dimethylphenyl) urea 140-141

48 l-Benzyl-l- [l- (3-methoxyphenyl) -2-phenyl-ethyl] -3- (3-trifluoromethylphenyl) urea 125-126

49 1-Benzyl-l- (n-pentyl) -3- (2,4-dimethylphenyl) urea oil

50 l-benzyl-l- (n-hexyl) -3- (2,4-dimethylphenyl) urea oil

51 l-Benzyl-l- (n-octyl) -3- (2,4-dimethylphenyl) urea oil

52 l-Benzyl-l- (n-undecyl) -3- (2,4-dimethylphenyl) urea oil

53 l-benzyl-l- (n-butyl) -3- (3-phenyl) thio-urea 83-85

54 l-benzyl-l- (n-butyl) -3- (3-chloro-2-methoxyphenyl) urea 52-54

55 l-Benzyl-l- (n-butyl) -3- (5-chloro-2-methoxyphenyl) urea 161-163

56 l- (n-butyl) -l- (2-fluorobenzyl) -3- (2,4-dimethylphenyl) urea 76-77

57 l- (n-butyl) -l- (4-fluorobenzyl) -3- (2,4-dimethylphenyl) urea 78-79

58 l- (n-butyl) -l- (2-chlorobenzyl) -3- (2,4-dimethylphenyl) urea 101-102

59 l- (n-butyl) -l- (2,6-dichlorobenzyl) -3- (2,4-dimethylphenyl) urea 145-146

60 l- (4-bromobenzyl) -l- (n-butyl) -3- (2,4-dimethylphenyl) urea 61-63

61 l- (n-butyl) -l- (4-n-butylbenzyl) -3- (2,4-dimethylphenyl) urea 60-62

62 l- (n-butyl) -l- (4-methylbenzyl) -3- (2,4-dimethylphenyl) urea oil

63 l- (n-butyl) -l- (4-tert-butylbenzyl) -3- (2,4-dimethyphenyl) urea 28-31

64 l- (n-butyl) -l- (4-chlorobenzyl) -3- (2,4-dimethylphenyl) urea oil

65 l- (n-butyl) -l- (4-methoxybenzyl) -3- (2,4-dimethylphenyl) urea oil

66 l- (n-butyl) -l- (3,4-methylenedioxybenzyl) -3- (2,4-dimethylphenyl) urea oil

67 l- (n-butyl) -l- (4-trifluoromethylbenzyl) -3- (2,4-dimethylphenyl) urea oil

68 l- (n-butyl) -l- (4-phenylbenzyl) -3- (2,4-dimethylphenyl) urea 82-83

69 l- (n-butyl) -l- (2-phenylethyl) -3- (2,4-dimethylphenyl) urea oil

70 l- (n-butyl) -l- [2- (4-fluorophenyl) ethyl] -3- (2,4-dimethylphenyl) urea oil

71 l- (n-Butyl) -l- [2- (4-chlorophenyl) ethyl] -3- (2,4-dimethylphenyl) urea oil

72 l- (n-Butyl) -l- [2- (3-methoxyphenyl) ethyl] -3- (2,4-dimethylphenyl) urea oil

73 l- (n-butyl) -3- (3-phenylpropyl) -3- (2,4-dimethylphenyl) urea oil

74 l- (n-butyl) -1- [4- (n-pentyl) benzyl] -3- (2,4-dimethylphenyl) urea 65-67

75 l- (n-butyl) -l-f4- (n-hexyl) benzyl] -3- (2,4-dimethylphenyl) urea oil

76 l- (n-butyl) -l- (3-chlorobenzyl) -3- (2,4-dimethylphenyl) urea oil

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Example 196 l-Benzyl-l- (n-butyl) -3- (phenyl) -urea A solution of 4.89 g of phenyl isocyanate in 100 ml of hexane becomes a solution of 4.41 g of N-benzyl-n-butylamine in 150 ml of 5 hexane added, the solution is stirred for 2 h at room temperature and then evaporated. The remaining solid is recrystallized from pentane; 1-Benzyl-l- (n-butyl) -3- (phenyl) urea is obtained.

st

Claims (8)

654 571 PATENT CLAIMS 1\ N Y ! I C. N R, R- 25th 3U 35 Y is selected from oxygen and sulfur; R! and R2 are identical or different and are independently selected from C4-] 2-alkyl, C4-12-alkenyl, C4-12-alkynyl, C4-12-cycloalkyl, C4-] 2-cycloalkylalkyl, Ct-14-aralkyl and C7-i4-aralkyl, in which an aromatic ring carries at least one substituent, selected from Ci-m-alkyl, Q-io-alkoxy, phenoxy, benzyloxy, methylenedioxy, Ci-4-alkyl-thio, phenyl, halogen, trihalomethyl, adamantyl , C [-4-carboalkoxy and nitro; and R3 is selected from hydrogen, C] -4-alkyl, C [-4-alkenyl, Q-Gt-alkynyl, benzyl, benzyl which carries at least one Z substituent, naphthyl, phenyl and phenyl which carries at least one Z substituent, where Z is selected independently of X and among the substituents from which X is selected and R! and R2 are different when R3 is hydrogen 40. 1. Compound of the formula N - C - N, / R1 R, (I) R 2. Connection according to claim 1, characterized in that Y stands for oxygen. 3. Connection according to claim 1, characterized in that X represents at least one halogen substituent. 4. Connection according to claim 1, characterized in that X represents at least one substituent selected from Cj-4-alkyl, C, -4-alkoxy, halogen, Q-4-carboalkoxy and benzyl. 5. A process for the preparation of the compounds mentioned in claim 1, characterized in that a compound of the formula Y R ^ s Y II N - C - B (VIII) to obtain and then the intermediate with a secondary amine of the formula in which: 10 X at least one substituent selected from hydrogen, Ci-4-alkyl, Q-4-alkenyl, Ci-4-alkynyl, hydroxy, Q-4-alkoxy, phenoxy, mercapto, Q-4-alkyl thio, amino, Q- , -Alkylamino, di- (Ci-4-alkyl) -amino, halogen, trihalomethyl, Q-4-alkanoyl, benzoyl, C ^ -alkanamido, C] -4-alkanesulfonyl-fonyl, Q-4-alkanesulfinyl, benzenesulfonyl , Toluenesulfonyl, Nitro, cyano, carboxy, Q-4-carboalkoxy, carbamoyl, sulfamoyl, methylenedioxy, phenyl, o-phenylene, tolyl, benzyl, halo-genbenzyl, methylbenzyl and the group 20th HN (IV) R .. wherein Ri and R2 have the meanings given in claim 1, implemented. 6. A process for the preparation of the compounds mentioned in claim 1, characterized in that a compound of the formula Y n A - C B (V) wherein Y has the meaning given in claim 1 and A and B are independently selected from halogen, C] -4-alkoxy, C] -4-alkylthio, phenoxy, 4-chlorophenoxy and 4-nitro-phenoxy; reacted with a secondary amine of the formula HN 'IV) R- wherein R [and R2 have the meanings given in claim 1 to an intermediate of the formula Y I! A - C - N R_ "R, (VI) to obtain, and the intermediate with an arylamine of the formula R-0 NH (VII) 45 implements, wherein X and R3 have the meanings given in claim 1. 7. Process for the preparation of compounds of the formula / R1 50 N - C - N \ R, (II) A - C - B (V) 55 wherein Y has the meaning given in claim 1 and A and B are independently selected from halogen, Q-4-alkoxy, Q-4-alkyIthio, phenoxy, 4-chlorophenoxy and 4-nitrophenoxy; reacted with an arylamine of the formula R, where X and Y have the meanings given in claim 1, R] and R2 are different and have the above meanings and R3 is hydrogen, characterized in that an aryl isocyanate or aryl thioisocyanate of the formula r; = r. = y 60 X (III) NH (VII) wherein X and R, which have the meanings given in claim 1, reacted with an intermediate of the formula with a secondary amine of the formula / R1 HN 'IV) -k2 654 571 where X, Y, R) and R2 have the meanings given above. 8. Pharmaceutical composition for the treatment of atherosclerosis, for reducing the cholesterol ester content of the arterial wall, for inhibiting the development of atherosclerotic lesion and / or for the treatment of hyperlipidemia in a mammal in need of such treatment, characterized by the content of an effective amount of A compound of formula I according to claim 1.