NL8300269A - SUBSTITUTED UREA AND THIOURUM COMPOUNDS WITH ANTIATHEROSCLEROTIC EFFICACY; METHOD FOR PREPARING THEREOF PHARMACEUTICAL PREPARATIONS WITH ANTIATHEROSCLEROTIC EFFECT; METHOD FOR TREATING ATHEROSCLEROSIS - Google Patents

Description

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VO 3990

Substituted urea and thiourea compounds with anti-atherosclerotic activity; method for preparing it; pharmaceutical preparations with anti-atherosclerotic activity? method of treating atherosclerosis.

The invention relates to substituted urea and thiourea compounds useful as pharmaceutical agents, some of which are new compounds. The compounds of the present invention are anti-atherosclerotic agents, which are capable of improving atherosclerosis by counteracting the formation or development of atheromatous lesions in the mammalian arterial walls. The invention also relates to the chemical preparation of the compounds described here. In addition, the invention relates to pharmaceutical compositions for the use of these compounds in mammalian disease treatment. Furthermore, the invention relates to methods of treating atherosclerosis in a manner aimed at preventing, stopping or reversing the course of the disease.

Several urea and thiourea compounds can be found in literature, for example, in J. Med. Chem. 18, 1024 (1975)? Chem. Absts. 95: 6758m (1981) and 91: 74631g (1979)? U.S. Patents 2,688,039? 3,335,142? 3,856,952? 3,903,130? and in German Offenlegungsschrift 29 28 485. The compounds found in the literature are described as useful herbicides, plant growth regulators, bactericides, pesticides, fungicides, algacides, photographic sensitizers, antihelmintics, sympatholytics, and anti-viral agents. The urea compounds described in German Offenlegungsschrift 29 28 485 are reported as useful for inhibiting lipid absorption. However, there are no publications describing the tetra-substituted urea and thiourea compounds of the present invention or their use in the treatment of atherosclerosis or hyperlipidemia.

Atherosclerosis is a form of arteriosclerosis characterized by lipid accumulation in and thickening of the arterial walls of both medium and large size arteries. The artery walls are thereby weakened and the.

83 0 0 26 9 ^ -------------- · '------------ t *' * -2- take elasticity and effective internal size of the artery off. Atherosclerosis is the most common cause of ischemic heart disease and is of great medical significance because the occlusion of medium and large sized arteries reduces the supply of blood to vital organs such as the heart muscles and brain.

The consequences of atherosclerosis include ischemic heart disease, cardiac arrest, life threatening arrhythmias, senility and stroke.

The fact that cholesterol is a major component of atherosclerotic lesions or sites has been known for over 100 years. Several researchers have studied the role of cholesterol in lesion formation and development and, more importantly, have also explored whether lesion formation can be prevented or lesion development halted or reversed. It is now known IMams, et al., Atherosclerosis, 13, 429 (1974)] that atheromatous lesions contain a greater amount of esterified cholesterol as opposed to unesterified cholesterol than the surrounding unaffected arterial wall. The intracellular esterification of cholesterol with fatty acids is catalyzed by the enzyme v'et-acyl CoA: cholesterol acyl transferase or ACAT and the accumulation and storage of 20 cholesteryl esters in the arterial wall is associated with an increased activity of this enzyme [Hashimoto and Dayton, Atherosclerosis, 28 447 (1977)]. In addition, cholesteryl esters are removed from cells more slowly than unesterified cholesterol. EBondjers and Bjorkerud, Atherosclerosis, 15, 273 (1972) and 22, 379 (1975)]. Inhibition of the ACAT enzyme would therefore decrease the rate at which the cholesterol is esterified, reduce the accumulation and storage of cholesteryl esters in the arterial wall, and prevent or inhibit the formation and development of atheromatous lesions. The compounds of the present invention are very potent inhibitors of the ACAT enzyme. These compounds are therefore useful for controlling and decreasing the cholesterol ester content of the mammalian artery walls, and for reducing the accumulation and storage of cholesterol in the mammalian artery walls. Furthermore, the compounds of the invention inhibit the formation or development of artherosclerotic lesions in mammals.

83 0 0 26 9 '. «* -3-

The evidence that hyperlipidemia is one of the factors involved in coronary heart disease is very impressive.

A very important study conducted in Framingham, Massachusetts (Cordon and Verter, 1969) in more than 5,000 subjects for more than 12 years showed an association between high concentrations of blood cholesterol and an increased risk of heart attack. Although there are many causes for coronary artery disease, one of the most constant factors is the increased concentration of lipids in the blood plasma. It has been shown (Carlson and Bottiger, 1972) that a combined increase in cholesterol and triglycerides poses the greatest risk for coronary heart disease. Most patients with ischemic heart disease or peripheral vascular disease have been shown to have hyperlipoproteinemia involving very low density and / or low density lipoproteins (Lewis, et al., 1974).

It has now been found that certain members of this class of compounds can safely and efficiently lower both serum lipids in warm-blooded animals. Such an effect on serum lipids is considered to be very useful for the treatment of atherosclerosis. For some time, it has been considered desirable to decrease the serum lipid levels and correct the disturbance of the lipDprctefre equilibrium in mammals as a preventative measure against atherosclerosis. The compounds of the present invention do not work by blocking late stages of cholesterol biosynthesis and therefore do not lead to an accumulation of intermediates such as desmosterol, which is as undesirable as cholesterol itself. Compounds with the combination of therapeutically beneficial properties possessed by the compounds of the present invention can be safely administered to warm-blooded mammals for the treatment of hyperlipidemic and atherosclerotic conditions, found in * 30 patients with or without susceptibility to heart attacks, for peripheral or cerebral vascular disease and for strokes.

The compounds of the invention exhibit anti-atherosclerotic activity and the invention is not limited to any particular mechanism of anti-atherosclerotic activity.

More particularly, the invention relates to certain new compounds, which may be represented by 8300269 * -4-Formula 1 of the formula sheet / wherein X represents at least one substituent selected from the group of hydrogen, alkyl of 1- 4 carbon atoms, alkenyl with 1-4 carbon atoms, alkynyl with 1-4 carbon atoms, hydroxy, alkoxy with 1-4 carbon atoms, phenoxy, mercapto, alkylthio with 1-4 carbon atoms, "amino, alkylamino with 1-4 carbon atoms, dialkylamino in which each alkyl group has 1-4 carbon atoms, halogen, trihalomethyl, alkanoyl with 1-4 carbon atoms, benzoyl, alkane amido with 1-4 carbon atoms, alkanesulfonyl with 1-4 carbon atoms, alkanesulfinyl with 1-4 carbon atoms, benzenesulfonyl, toluene sulfonyl, nitro, cyano, carboxy, carboalkoxy of 1-4 carbon atoms, carbamoyl, sulfamyl, methylenedioxy, phenyl, ortho-phenylene, tolvl, benzyl, halobenzyl, methylbenzyl and the group of formula 2, wherein Y is selected from the group oxygen and sulfur; and Rj are the same or different and are independently selected from the group 15 alkyl of 4-12 carbon atoms, alkenyl of 4-12 carbon atoms, alkynyl of 4-12 carbon atoms, cycloalkyl of 4-12 carbon atoms, cycloalkylalkyl of 4-12 carbon atoms, aralkyl of 7-14 carbon atoms and aralkyl of 7-14 carbon atoms, in which an aromatic ring carries at least one substituent selected from the group of alkyl 20 having 1-10 carbon atoms, alkoxy having 1-10 carbon atoms, phenoxy, benzyloxy, methylenedioxy, alkylthio of 1-4 carbon atoms, phenyl, halogen, trihalomethyl, adamantyl, carboalkoxy of 1-4 carbon atoms, and nitro; R ^ is selected from the group of hydrogen, alkyl of 1-4 carbon atoms, alkenyl of 1-4 carbon atoms, alkynyl of 1-4 carbon atoms, benzyl, benzyl with at least one substituent Z, naphthyl, phenyl and phenyl with at least one substituent Z, wherein Z is independently selected from X from the group from which X is selected. Preferred embodiments of the invention are those wherein Y is oxygen. More preferred are those compounds wherein X 30 represents at least one alkyl group of 1 to 4 carbon atoms or halogen substituent and R 4 are the same or different and are independently selected from the group of alkyl of 4-12 carbon atoms, aralkyl of 7-14 carbon atoms and substituted aralkyl of 7-14 carbon atoms. Most preferred are those compounds in which X is at least 35 a methyl or chlorine substituent and Z is hydrogen, methyl or chlorine.

8300269 - -5- 'Fr- • * j *

The invention further relates to a process for preparing compounds of formula la, wherein X represents at least one substituent selected from the group consisting of hydrogen, alkyl of 1-4 carbon atoms, alkenyl of 1-4 carbon atoms, alkynyl of 1-4 5 carbon atoms, hydroxy, alkoxy of 1-4 carbon atoms, phenoxy, mercapto, alkylthio of 1-4 carbon atoms, amino, alkylamino of 1-4 carbon atoms, dialkylamino in which each alkyl group has 1-4 carbon atoms, halogen, trihalomethyl, alkanoyl with 1-4 carbon atoms, benzoyl, alkane amido with 1-4 carbon atoms, alkanesulfonyl with 1-4 carbon atoms, alkanesulfinyl with 1-4 carbon atoms, benzenesulfonyl, toluenesulfonyl, nitro, cyano, carboxy, carboalkoxy with 1-4 carbon atoms, carbamoyl sulfamyl, methylenedioxy, phenyl, ortho-phenylene, tolyl, benzyl, halobenzyl, methylbenzyl, and the group of formula 2a, Y is selected from the group of oxygen and sulfur; and R 2 are the same or different and are independently selected from the group of alkyl of 4-12 carbon atoms, alkenyl of 4-12 carbon atoms, alkynyl of 4-12 carbon atoms, cycloalkyl of 4-12 carbon atoms, cycloalkylalkyl of 4-12 carbon atoms, aralkyl of 7-14 carbon atoms, and aralkyl of 7-14 carbon atoms, in which an aromatic ring bears at least one substituent selected from the group of alkyl of 1-10 carbon atoms, alkoxy of 1-10 carbon atoms, phenoxy, benzyloxy, methylenedioxy, alkylthio with 1-4 carbon atoms, phenyl, halogen, trihalomethyl, adamantyl, carboalkoxy of 1-4 carbon atoms, and nitro; wherein an aryl isocyanate or aryl thioisocyanate of formula 3 is reacted with a secondary amine of formula 4, wherein the symbols X, Y, R1 and R2 are as defined above.

A specific method of preparing the compound of formula la includes reacting a compound of formula 5 wherein Y is as defined in formula la and A and B are independently selected from the group of halogen, alkoxy of 1-4 carbon atoms, alkylthio of 1-4 carbon atoms, phenoxy, 4-chlorophenoxy, and 4-nitrophenoxy, with a secondary amine of formula 4, wherein R 1 and R 2 are as defined in formula 1a to form an intermediate of formula 6 and the then reacting the intermediate with an arylamine of formula 7, wherein X is as defined in formula 1a.

83 0 0 2 6 9: - * ♦ -6-

Yet another specific method of preparing the compounds of formula la comprises reacting a compound of formula 5, wherein Y is as defined in formula la and A and B are independently selected from the group of halogen, alkoxy with 5-1 4 carbon atoms, alkylthio of 1-4 carbon atoms, phenoxy, 4-chlorophenoxy, and 4-nitrophenoxy, with an arylamine of formula 7, wherein X is as defined in formula 1a, to form an intermediate of formula 8, and then reacting the intermediate with a secondary amine of formula 4, wherein and are as defined in formula 1a.

The invention relates to a method of treating atherosclerosis, decreasing arterial wall cholesterol ester content, inhibiting the development of atherosclerotic lesions, and / or treating hyperlipidemia in a mammal in need of such treatment wherein the mammal is administered an effective amount of a compound of formula 1, wherein X represents at least one substituent selected from the group consisting of hydrogen, alkyl, having 1-4 carbon atoms, alkenyl having 1-4 carbon atoms, alkynyl having 1-4 carbon atoms, hydros, 20 alkoxy with 1-4 carbon atoms, phenoxy, mercapto, alkylthio with 1-4 carbon atoms, amino, alkylamino with 1-4 carbon atoms, dialkylamino in which each alkyl group has 2-4 carbon atoms, halogen, trihalogen methyl, alkanoyl of 1-4 carbon atoms, benzoyl, alkanamido of 1-4 carbon atoms, alkanesulfonyl of 1-4 carbon atoms, alkanesulfinyl of 1-4 carbon atoms, benzee sulfonyl, toluenesulfonyl, nitro, cyano, carboxy, carboalkoxy of 1-4 carbon atoms, carbamoyl, sulfamyl, methylenedioxy, phenyl, ortho-phenylene, tolyl, benzyl, halobenzyl, methylbenzyl, and the group of formula 2, Y is selected from the group oxygen and sulfur; R 1 and R 2 are the same or different and are independently selected from the group of alkyl of 4-12 carbon atoms, alkenyl of 4-12 carbon atoms, alkynyl of 4-12 carbon atoms, cycloalkyl of 4-12 carbon atoms, cycloalkylalkyl of 4-12 carbon atoms, aralkyl of 7-14 carbon atoms, and aralkyl of 7-14 carbon atoms in which an aromatic ring carries at least one substituent selected from the group of alkyl of 1-10 carbon atoms, alkoxy of 1-10 carbon atoms, phenoxy benzyloxy, methylenedioxy, alkylthio of 8300269 * -7-1-4 carbon atoms, phenyl, halogen, trihalomethyl, adamantyl, carboalkoxy of 1-4 carbon atoms, and nitro; and R 4 is selected from the group consisting of hydrogen, alkyl of 1 to 4 carbon atoms, alkenyl of 1 to 4 carbon atoms, alkynyl of 1 to 4 carbon atoms, benzyl, benzyl with at least a substituent of Z, naphthyl, phenyl, and phenyl with at least one substituent Z in which Z is independently selected from X from the group from which X is selected.

Finally, the invention relates to a pharmaceutical preparation and the preparation thereof, which preparation is suitable for treating atherosclerosis, lowering the cholesterol ester content of the arterial wall, inhibiting the development of atherosclerotic lesions, and / or treating hyperlipidemia in a mammal in need of such treatment, said composition comprising an effective amount of a compound of formula 1, wherein X represents at least one substituent selected from the group of hydrogen, alkyl of 1-4 carbon atoms , alkenyl with 1-4 carbon atoms, alkynyl with 1-4 carbon atoms, hydroxy, alkoxy with 1-4 carbon atoms, phenoxy, mercapto, alkylthio with 1-4 carbon atoms, amino, alkylamino with 1-4 carbon atoms, dialkylamino where Each alkyl group contains 1-4 carbon atoms, halogen, trihalomethyl, alkanoyl of 1-4 carbon atoms, benzoyl, alkanamido of 1-4 carbon atoms, alkanesulfonyl of 1-4 carbon tof atoms, alkanesulfinyl of 1-4 carbon atoms, benzenesulfonyl, toluene sulfonyl, nitro, cyano, carboxy, carboalkoxy of 1-4 carbon atoms, carbamoyl, sulfamyl, methylenedioxy, phenyl, ortho-phenylene, tolyl, benzyl, halobenzyl, methylbenzyl , and the group of formula 2, Y is selected from the group of oxygen and sulfur; and are the same or different and are independently selected from the group of alkyl of 4-12 carbon atoms, alkenyl of 4-12 carbon atoms, alkynyl of 4-12 carbon atoms, cycloalkyl of 4-12 carbon atoms, cycloalkylalkyl of 4-12 carbon atoms, aralkyl of 7-14 carbon atoms, and aralkyl of 7-14 carbon atoms in which an aromatic ring bears at least one substituent selected from the group of alkyl of 1-10 carbon atoms, alkoxy of 1-10 carbon atoms, phenoxy, benzyloxy, methylthio with 1-4 carbon atoms, phenyl, halogen, trihalomethyl, adamantyl, carboalkoxy of 1-4 carbon atoms, and nitro; and R 4 is selected from the 8300269-8 group hydrogen, alkyl of 1 to 4 carbon atoms, alkenyl of 1 to 4 carbon atoms, alkynyl of 1 to 4 carbon atoms, benzyl, benzyl with at least one substituent Z, naphthyl, phenyl, and phenyl with at least one substituent Z, wherein Z is independently selected from X from the group 5 from which X is selected; as well as a non-toxic, pharmaceutically acceptable carrier.

. Certain urea and thiourea compounds of the invention are prepared by reacting activated carboxylic acid derivatives such as phosene, thiophosene, or phenyl chloroformate with secondary amines to yield an intermediate, which is, for example, a two-substituted carbamyl chloride. This intermediate is in turn reacted with an arylamine to yield the urea or thiourea compound. The preparation of the intermediate is carried out in an aprotic solvent, such as tetrahydrofuran, toluene, xylene, and the like at temperatures from about room temperature to the boiling point of the solvent. The intermediate can be isolated by evaporation and, if desired, purified by distillation. The intermediate is then reacted with an arylamine 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 method is the reaction of phosgene with N-benzyl-n-butylamine in toluene to yield the intermediate N-benzyl-N- (n-butyl) carbamyl chloride, which intermediate is then reacted with diphenylamine in Ν, Ν-dimethylacetamide in the presence of sodium hydride to give 1-benzy1-1- (n-butyl) -3,3-diphenylurea.

Other urea and thiourea compounds of the invention are prepared by reacting arylamines with activated carboxylic acid derivatives such as phosgene or thiophosgene to form an intermediate, eg, an aryl carbamyl chloride. This intermediate is then reacted with a secondary amine to form the urea or thiourea compound. The preparation of this intermediate is carried out in an aprotic solvent such as tetrahydrofuran, toluene or xylene at temperatures from about room temperature up to the boiling point of the solvent in the presence of a base, for example N, N-dimethylaniline. The intermediate is then reacted with a secondary amine 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 method is the reaction of phosgene with N-phenyl-3-chloroaniline to form the intermediate N- (3-chloro-phenyl) -N-phenylcarbamyl chloride, which intermediate then with N-benzyl-n-butylamine is reacted to form 1-benzyl-1- (n-butyl) -3- (3-chlorophenyl) -3-phenylurea.

The urea and thiourea compounds of the invention containing carboxyl groups are prepared by basic hydrolysis of the corresponding carboalkoxy urea and thiourea compounds prepared according to the synthetic methods described above.

Likewise, the compounds containing hydroxyl, mercapto or amino groups are prepared by basic hydrolysis of the corresponding O-acetyl, S-acetyl, and N-acetylurea and thiourea compounds, the latter being also obtained by the urea syntheses described above and thiourea compounds.

Alternatively, urea and thiourea compounds containing hydroxy1-20 groups can be prepared by cleaving the corresponding methoxy compounds using Lewis acids such as boron tribromide.

Certain substituted N-benzylanilines, which are required intermediates for the synthesis of some of the new tetra-substituted urea and thiourea compounds of this invention, are not known. The required N-benzylanilines are prepared by reacting various benzaldehydes with anilines to form anil.

The anils are then reduced to yield the substituted N-benzylanilines. An example of such a synthesis includes the reaction of 2,4-dimethylbenzaldehyde with 2,4-dichloroaniline to yield N- (2,4-dimethylbenzylidene) -2,4-dichloroaniline, followed by reduction with sodium borohydride to give N- ( 2,4-dimethylbenzyl) -2,4-dichloroaniline is obtained.

Many of the urea and thiourea compounds of the invention are prepared by reacting aryl isocyanates and aryl isothiocyanates with secondary amines. These responses can be 8 3 0 0 26 9 '.....

- performed 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 evaporation of the solvent, and they can be purified by recrystallization, absorption chromatography, or distillation under reduced pressure. An example of this method is the reaction of 2,4-dimethylphenyl isocyanate with di- (n-butyl) amine to form 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 of the invention are prepared by diborane reductions of the corresponding amides. An example of this reaction is the synthesis of N- (n-butyl) -2-chloro-benzylamine by diborane reduction of N- (n-butyl) -2-chlorobenzamide.

Some of the amides required for these reductions are prepared by acylation of primary amines with carboxylic acids by methods well known to those skilled in the art, for example, conversion of the carboxylic acid to the corresponding carboxylic acid chloride using thionyl chloride and then reaction of the acid -20 chloride with the primary amine in the presence of a base.

A very suitable method for this conversion is the reaction of a carboxylic acid with a primary amine catalyzed by boron trifluoride etherate. An example of this conversion is the acylation of 2-chlorobenzylamine 25 with 3-methoxyphenylacetic acid catalyzed by boron trifluoride etherate to form N- (2-chlorobenzyl) -3-methoxyphenylacetamide.

The urea and thiourea compounds of the present invention are represented as crystalline solids or as distillable liquids. They are characterized by different melting or boiling points and unique spectra. They are quite soluble in organic solvents, but generally less soluble in water. The compounds containing carboxylic acid groups can be converted to the alkali metal and alkaline earth metal salts by treatment with the appropriate metal hydroxides, and those containing amino-35 groups can be converted to the ammonium salts by treatment with organic or inorganic acids. Both types of salts show a higher water solubility.

83 0 0 2 6 9 "-π-

The properties and utility of the compounds of the invention will be explained in conjunction with the specific tables shown below.

The compounds of the present invention were analyzed 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 acyl C0A: cholesterol acyl transferase (ACAT) and were tested in vitro for serum hypolipidemic activity as measured by their ability to inhibit lipid absorption in rats.

The compounds were tested for their ability to inhibit ACAT in accordance with the following procedure:

Rat adrenal glands were homogenized in 0.2½ potassium phosphate monobasic buffer, pH 7.4, and at 5 ° C for 15 minutes.

15 centrifuged 1000 times gravity. The supernatant containing the microsomal fraction served as the source of the cholesterol esterification enzyme, fatty acyl CoA: cholesterol acyl transferase (ACAT). A mixture containing 50 parts of the adrenal supernatant, 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. Pre-incubated at 37 ° C for 10 minutes. After treatment with 20 parts of oleoyl CoA (C-0.4 Ci), the mixture was incubated at 37 ° C for 10 minutes. A control mixture omitting the test compound was prepared and treated in the same manner. The lipids were extracted from the incubation mixture in an organic solvent and separated by thin layer chromatography. The cholesterol ester fraction was counted in a scintillation counter. This procedure is a modification of the procedure described by Hashimoto, et al., Life Science, 12 (part II), 1-12 (1973).

The results of this test of representative compounds of the invention are shown in Table A below.

....... 830 0 269 35 -12-

Table A

Compound% Inhibition 1-Benzyl-1- (n-butyl) -3,3-diphenylurea 75,9 1-Benzyl-1- (n-butyl) -3- (3-chlorophenyl) -3-phenylurea 72.3 5 1-Benzyl-1- (n-butyl) -3- (2-naphthyl) -3-phenylurea 83,6 1-Benzyl-1- (n-butyl) -3-benzyl-3-phenylurea 81,8 1- Benzyl-1- (n-butyl) -3-6-methylpheny1) -3-phenylurea 82.0 1-Benzyl-1- (n-butyl) -3- (3-methoxyphenyl) -3-phenylurea 82.5 1 -Benzyl-1- (n-butyl) -3- (4-isopropoxyphenyl) -3-phenylurea 77,8 10 1-Benzyl-1- (n-butyl) -3- (1-naphthyl) -3-phenylurea 76 .3 1-Benzyl-1- (n-butyl) -3- (2-naphthyl) -3- (3-chlorophenyl) urea 82,7 1-Benzyl-1- (n-butyl) -3,3-di - (2-naphthyl) urea 93,12 1,3-Dibenzyl-1,3-di- (n-butyl) urea 95,4 1-Benzyl-1- (n-butyl) -3- (3-methylphenyl) urea 93'3 15 1-Benzyl-1- (n-butyl) -3- (3-trifluoromethylphenyl) urea 85,7 1-Benzyl-1- (n-butyl) -3- (3,5-dichlorophenyl) urea 99'7 1-Benzyl-1- (n-butyl) -3- (3,4-dichlorophenyl) urea 93'-1-Benzyl-1- (n-butyl) -3- (3-chlorophenyl) urea 88.6 1-Benzyl-1- (n-butyl) -3- (2,4-dimethylphenyl) urea 91,3 20 1-Benzyl-1- (n-butyl) -3- (2-methylphenyl) urea 78.8 1-Benzyl-1- (n-buty l) -3- (4-methylphenyl) urea '78'9 1-Benzyl-1- (n-butyl) -3- (2,3-dimethylphenyl) urea 85' 8 1-Benzyl-1- (n- butyl) -3- (2,5-dimethylphenyl) urea 937 1-Benzyl-1- (n-butyl) -3- (2,6-dimethylphenyl) urea 83,1 1-Benzyl-1- (n -butyl) -3- (3,5-dimethylphenyl) urea 94.2 1-Benzyl-1- [1- (3-methoxyphenyl) -2-phenylethyl] - 3- (2,4-dimethylphenyl) urea 86.4 1-Benzyl-1- [1- (4-benzyloxyphenyl) -2-phenylethyl] - 3- (2,4-dimethylphenyl) urea 93.0 30 1-Benzyl-1- (1,2-diphenylethyl) -3- (2,4-dimethyl-phenyl) urea 95.0 1-Benzyl-1- (n-butyl) -3- (3,4-dimethylphenyl) urea 87'-1-Benzyl-1- [1- (3- methoxyphenyl) -2-phenylethyl] - 3- (3-trifluoromethylphenyl) urea 88 '* 35 1-Benzyl-1- (n-butyl) -3- (3-chloro-2-methoxyphenyl) urea 8 ^' 3 ............ -83 0 0 m ------------------— - ............. ...... ....................

-13- 1-Benzyl-1- (n-butyl) -3- (5-chloro-2-methoxyphenyl) urea 80,6 1-Benzyl-1- (n-butyl) -3-phenylthiourea 82,4 1- (n-Butyl) -1- (2-fluorobenzyl) -3- (2,4-dimethylphenyl) urea 82.6 1- (n-Bufcyl) -1- (4-fluorobenzyl) -3- (2,4- dimethylphenyl) urea 80.6 5 1- (n-Butyl) -1- (2-chlorobenzyl) -3- (2,4-dimethylphenyl) urea 95.5 1- (n-Butyl) -1- (2.6 -dichlorobenzyl) -3- (2,4-dimethyl-1-phenyl) urea 74.5 1- (n-Butyl) -1- (4-bromobenzy1) -3- (2,4-dimethylphenyl) urea 81.0 1 - (n-Butyl) -1- [4- (n-butyl) benzyl) 3 -3- (2,4-dimethyl Ι-ΙΟ phenyl) urea 94.4 l- (n-Butyl) -1- (4 -methylbenzyl) -3- (2,4-dimethylphenyl) urem 96.7 1- (n-Butyl) -1- (4-tert-rbutybenbenzy 1) - 3- (2,4-dimethyl- = phenylurea 96, 4 1- (n-Butyl) -1- (4-chlorobenzyl) -3- (2,4-dimethylphenyl) urea 94,6 15 1- (n-Butyl) -1- (4-methoxybenzyl) -3- ( 2,4-dimethylphenyl) urea 94f2 1- (n-Butyl) -1- (3,4-methylenedioxybenzy1) -3- (2,4-dimethylphenyl) urea 88.2 1- (n-Butyl) -1- ( 4-Trifluoromethylbenzy1) -3- (2,4-dimethylphenyl) urea 93,3 20 1- (n-Butyl) -1- (4-phenylbenzyl) -3- (2,4-dimethylphenyl) urea m 97.1 1- (n-Decyl) -1-benzyl-3- (2,4-dimethylphenyl) urea 96.1 1- (n-Butyl) -1- (2-phenylethyl) -3- (2, 4-dimethylphenyl) urea 87.9 1- (n-Butyl) -1- [2- (4-fluorophenyl) ethyl] -3- (2,4-dimethyl-1-phenyl) urea 96.1 25 1- (n- Butyl) -1- [2- (4-chlorophenyl) ethyl] -3- (2,4-dimethylphenyl) urea 93.3 1- (n-Butyl) -1- [2- (3-methoxyphenyl) ethyl] -3- (2,4-dimethylphenyl) urea 89.3 1- (n-Butyl) -1- (3-phenylpropyl) -3- (2,4-dimethylphenyl) urea 97.4 30 1- (n-Butyl 1-benzyl-3- (2,4,6-trimethylphenyl) urea 75.8 1- (n-Butyl) -1- [4- (n-hexyl) benzyl] -3- (2,4-dimethyl) - phenyl) urea 93.8 1- (n-Tetradecyl) -1-benzyl-3- (2,4-dimethylphenyl) urea 80,3 1- (n-Octadecyl) -1-benzyl-3- (2,4 -dimethylphenyl) urea 80.3 35 1- (n-Octadecyl) -1-benzyl-3- (2,4-dimethylphenyl) urea 19.7 1- (n-Butyl) -1- [2- (3-bromophenyl) ) ethyl] -3- (2,4-dimethylphenyl) urea 97.0 1.1-Dibenzyl-3- (2,4-dimethylphenyl) urea 89.9 1.1- Dibenzyl-3- (2-methylphenyl) urea 77.0 8300269 -14- 1.1- Dibenzyl-3- (3-methylphenyl) urea 88.9 1.1- Dibenzyl-3- (4-methylphenyl) urea 86.5 1.1- Dibenzyl-3- (4-n-butylphenyl) urea 91.3 1.1- Dibenzyl-3- (2,3-dimethylphenyl) urea 88.1 5 1,1-Dibenzy1-3- (2,5-dimethylphenyl) urea 89/1 1.1- Dibenzyl-3- (2,6 -dimethylphenyl) urea 56.1 1.1- Dibenzyl-3- (3,4-dimethylpheny1) urea 71.8 1.1- Dibenzyl-3- (3,5-dimethylphenyl) urea 90.2 1.1- Dibenzyl-3- (2, 4,6-trimethylphenyl) urea 36.9 10 1.1-Dibenzyl-3- (4-methoxyphenyl) urea 71.6 1.1-Dibenzyl-3- (4-n-butoxyphenyl) urea 90.2 1.1-Dibenzyl-3 - (4-Methylthiophenyl) urea 67.1 1.1-Dibenzyl-3- (2-chlorophenyl) urea 87.8 1.1- Dibenzyl-3- (3-chlorophenyl) urea 94.2 15 1, 1-Dibenzyl-3- ( 4-chlorophenyl) urea 77.5 1.1- Dibenzyl-3- (2-bromophenyl) urea 93.9 1.1- Dibenzyl-3- (4-bromophenyl) urea 79.9 1,1-Dibenzyl-3- (4-y .odophenyl) urea 85.2 1.1-Dibenzyl-3- (2,3-dichlorophenyl) urea 79.7 20 1,1-Dibenzyl-3- (2,4-dichlorophenyl) urea 83,3 1,1-Dibenzyl-3 - (2,5-dichlorophenyl) urea 82.4 1.1- Dibenzyl-3- (3,5-dichlorophenyl) urea 86.1 1.1- Dibenzyl-3- (3-trifluoromethylphenyl) urea 94.2 1.1- Dibenzyl-3- (3-acetylphenyl) urea 80.7 25 1, 1-Dibenzyl-3- (4-phenoxyphenyl) urea 94.3 1. 1- Dibenzyl-3- (3-chloro-2-methylphenyl) urea 83,8 1.1- Dibenzyl-3- (3-chloro-4-methylphenyl) urea 94,0 1.1- Dibenzyl-3- (4-chloro-3 -trifluoromethylpheny1) urea 92.0 1.1- Dibenzyl-3- (4-chloro-2-trifluoromethylphenyl) urea 81.8 30 1.1-Dibenzyl-3- (3-methylphenyl) triourea 71.2 1.1-Dibenzyl-3- (3-Bromophenyl) urea 91.9 1.1-Dibenzyl-3- (2,3-dibenzophenyl) urea 90.0 1.1-Dibenzyl-3- (5-chloro-2-methylphenyl) urea 71.3 1.1-Dibenzyl-3 - (3-methoxyphenyl) urea 87.0 35 1.1-Dibenzyl-3- (2-methoxyphenyl) urea 91.0 1.1- Dibenzyl-3- (3-nitrophenyl) urea 81.3 83 0 0 "26 9 - ---------------------- ”-15- 1.1- Dibenzyl-3- (2,5-dimetphoxyphenyl) urea 87.9 1.1- Dibenzyl-3- ( 2,6-dichlorophenyl) urea 88,6 1,1-Dibenzyl-3- (3,4-dichlorophenyl) urea 94,5 1,1-Dibenzyl-3- (4-chloro-2-methylphenyl) urea 62.7 5 1 1,1-Dibenzyl-3- (2-methoxy-5-methylphenyl) urea 87.8 1,1-Dibenzyl-3- (6-chloro-2-methylphenyl) urea 83,9 1,1-Dibenzyl-3- (6- ethyl 2-methylphenyl) urea 73.6 1.1-Dibenzyl-3- (2,6-diethylphenyl) urea 72.0 1.1-Dibenzyl-3- (2,6-isop ropylphenyl) urea 59.1 10 1.1-Dibenzyl-3- (4-nitrophenyl) urea 52.2 1.1-Dibenzyl-3- (4-ethoxyphenyl) urea 95.8 1.1-Dibenzyl-3- (2, 5-difluorophenyl) urea 72.0 1.1-Dibenzyl-3- (2,4-dibromophenyl) urea 81,9 1.1-Dibenzyl-3- (3-chloro-4-methylphenyl) thiourea 94,1 15 1,1-Dibenzyl -3- (2,4-dimethylphenyl) thiourea 78.7 1,1-Dibenzyl-3- (3-trifluoromethylphenyl) thiourea 88,6 1,1-Dibenzyl-3- (2,4,5-trimethylphenyl) urea 69.1 1.1- Dibenzyl-3- (phenyl-4-carboxylic acid) thiourea ethyl ester 76.6 1.1- Dibenzyl-3- (3,4-dibenzophenyl) urea 97,3 20 1,1-Dibenzyl-3- (2-trifluoromethylphenyl) urea 68 .4 1.1- Dibenzyl-3- (4-methylphenyl) urea 89.8 1.1- Dibenzyl-3-phenylurea 90.4 1.1- Dibenzyl-3- (4-carboxyphenyl) urea 14.1 1.1- Dibenzyl-3- {4 -carbethoxyphenyl) urea 94.9 25 1-Benzyl-1- (n-butyl) -3- (phenyl) urea 82.0 1.1-di * (n-butyl) -3- (2,4-dimethylpheny1) urea 81.1 1.1-di- {n-butyl) -3- (2-methylphenyl) urea 61.8 1.1-cLHn-butyl) -3- (3-methylphenyl) urea 78.4 1.1-di- (n-butyD -3- (4-methylphenyl) urea 79.9 30 1,1-di- (n-butyl) -3 - (4-N-butylphenyl) urea 93.5 1.1-di- (n-butyl) -3- (2,3-dimethyl Ifenyl) urea 87,6 1,1-di- (n-butyl) -3- (2 1,5-dimethylphenyl) urea 96.1 1,1-di- (n-butyl) -3- (2,6-dimethylphenyl) urea 85,3 1,1-di- (n-butyl) -3- (3,4-dimethylphenyl ) urea 49.2 35 1,1-di- (n-butyl) -3- (3,5-dimethylphenyl) urea 83.5 1,1-di- (n-butyl) -3- (2,4,6- trimethylphenyl) urea 73.4 8300269 “if * -16- 1.1-di- (n-butyl) -3- (4-methoxyphenyl) urea 58,7 1,1-di- (n-buty1) -3- (4-ethoxyphenyl urea 78.6 1.1-di- (n-butyl) -3- (3-methylthiophenyl) urea 84.7 1,1-di- (n-butyl) -3- (2-chlorophenyl) urea 71.0 5 1, 1-di- (n-butyl) -3- (3-chlorophenyl) urea 88.3 1,1-di- (n-butyl-3- (3-bromophenyl) urea 86,0 1,1-di- (n -butyl) -3- (4-fluorophenyl) urea 55,9 1,1-di- (n-butyl) -3- (4-iodophenyl) urea 83,1 1,1-di- (n-butyl) -3- (2 , 3-dichlorophenyl) urea 71,8 10 1,1-di- (n-butyl) -3- (2,4-dichlorophenyl) urea 70,0 1,1-di- (n-buty 1) -3- (3 , 5-dichlorophenyl) urea 79,3 1,1-di- (n-butyl) -3- (3-trifluoromethylphenyl) urea 75.0 1,1-di- (n-butyl) -3- (3-acetylphenyl) urea 50.9 1. 1- di- (n-butyl) -3- (4-acetylphenyl) urea 55.1 15 1,1-di- (n-butyl) -3- (3-chloro-2-methylphenyl) urea 80.2 1.1 - di- (n-butyl) -3- (3-chloro-4-methylphenyl) urea 91.2 1.1-di- (n-butyl) -3- (3-chloro-4-fluorophenyl) urea 90.9 1.1 - di- (n-butyl) -3- (2-chloro-4-nitrophenyl) urea 86,7 1,1-di- (n-butyl) -3- (4-chloro-3-trifluoromethylphenyl) urea 87, 3 20 1,1-di- (sec-butyl) -3- (2,4-dimethylphenyl) urea 78.1 1,1-di- (n-pentyl) -3- (2,4-dimethylphenyl) urea 90.3 1.1-di- (isopentyl) -3- (2,4-dimethylphenyl) urea 88.7 1,1-di- (n-hexyl) -3- (2,4-dimethylphenyl) urea 95.1 l, 1-di - (n-heptyl) -3- (2,4-dimethylphenyl) urea 91.1 25 1,1-di- (n-decyl) -3- (2,4-dimethylphenyl) urea 64.0 1.1 - di- (ii-octy 1) -3- (2,4-dimethylphenyl) urea 88,6 1,1-di- (4-cyclohexyl-n-buty 1) -3- (2,4-dimethylphenyl) urea 86.3 1.1-di- (cyclopentyl) -3- (2,4-dimethylphenyl) urea 90.4 1.1-di- (n-butyl) -3- (2,3-dibenzophenyl) urea 85.1 30 1 1,1-di- (n-butyl) -3- (4-chloro-2-methylphenyl) urea 88.0 1, 1-dicyclohexyl-3- (2,4-dimethyl If enyl) urea 94.3 1. 1- di- (n-butyl) -3- (3-methoxyphenyl) urea 77.1 1,1-di- (n-butyl) -3- [(3,3-dibutyl) urea-4-methylphenyl] urea 94, 5 1.1- di- (ii-butyl) -3- (2,3,5-trichlorophenyl) urea 61,6 35 1,1-di- (isobutyl) -3- (2-chlorophenyl) urea 35,4 1.1- di- (isobutyl) -3 - [(3,3-diisobutyl) urea-4-methylphenyl)] urea 94.7 8 3 0 0 2 6 9 »-17- ',' Ί \ 1.1-di- (isobutyl) -3- (2,5-dimethylphenyl) urea 74,3 1,1-di- (isobutyl) -3- (2,6-dimethylphenyl) urea 41,2 1,1-di- (n-butyl) -3- (5- chloro-2-methylphenyl) urea 75,3 1,1-di- (n-butyl) -3- (4-n-butylphenyl) urea 93,5 5 1,1-di- (n-butyl) -3- (4 -isopropylphenyl) urea 76.4 1.1-di- (3,5,5-trimethylhexy1) -3- (2,4-dimethylphenyl) urea 90.4 1,1-di- (2-ethylhexyl) -3- (2 , 4-dimethylphenyl) urea 86.2 1.1-di- (n-nonyl) -3- (2,4-dimethylphenyl) urea 90.0 10 1,1-di- (n-undecyl) -3- (2 , 4-dimethylphenyl) urea 48,9 1,1-di- (n-dodecyl) -3- (2,4-dimethylphenyl) urea 26,3 1- [2- (3,4-dimethoxyphenyl) ethyl] -1- ( 3-chloro-4-methylbenzyl) -3- (2,4-dimethylphenyl) urea 53,3 1- [2- (2-methylphenyl) ethyl] -1- (4-bromobenzyl ) -15 3- (2,4-dimethylphenyl) urea 29.2 1- [2- (3-trifluoromethylphenyl) ethyl] -1- (2-chlorobenzyl) -3- (2,4-dimethylphenyl) urea 7 8 1- (2-fluorobenzyl) -1- (2-methoxybenzyl) - 3- (2,4-dimethylphenyl) urea 41.5 20 1— C2— (3,4-dimethoxyphenyl) ethyl] -1- (4 -fluorobenzyl) - 3- (2,4-dimethylphenyl) urea 57.4 1- [2- (4-ethoxyphenyl) ethyl] -1- (2,4-dimethylbenzyl) - 3- (2,4-dimethylphenyl) urea 34.9 1- [2- (3-methylphenyl) ethyl] -1- (3-nitrobenzyl) -25 3- (2,4-dimethylphenyl) urea 95.7 1- [2- (2,5-dimethoxyphenyl) ethyl ] -1- (3-chlorobenzyl) -3- (2,4-dimethylphenyl) urea 97.1 1- (n-butyl) -1- (2-methyl 1-2,2-diphenyl) ethyl- 3- (2,4-dimethylphenyl) urea 97.4 30 1- (n-butyl) -1- {4-hexyloxybenzy1) -3- (2,4,6-trimethylphenyl) urea 97.1 1- ( n-butyl) -1- (4-heptyloxybenzyl) -3- (2,4,6-trimethylphenyl) urea 97,3 1- (n-butyl) -1-benzyl-3- (4-trifluoroacetyl-35 amino- 3,5-dichlorophenyl) urea 87.8 1-benzyl-1- (4-n-butylbenzyl) -3- (2,4-dimethylphenyl) urea 91,9 1-benzyl-1- (4-n-butylbenzyl) -3- (2,4,6-trimethylphenyl) urea 92.8 40 1-benzyl-1- (4-n-buty lbenzyl) -3- (4-n-butylphenyl) urea 92.0 830 0 269 ----------------------------- - -------- -18- 1-benzyl-1- (4-n-butylbenzyl) -3- (4-phenoxyphenyl) urea 93.5 1- (n-heptyl) -1- (4-n -butylbenzyl) -3- (2,4-dimethyl-phenyl) urea 94.8 1- (n-heptyl) -1- (4-n-butylbenzyl) -3- (2,4,5-tri-5-methylphenyl ) urea 95.3 1-benzyl-1- [2-phenyl-1- (4-benzyloxyphenyl) ethyl] - 3- (2,4,5-trimethylphenyl) urea, 93.7 1- (n-heptyl) - 1- (4-butyloxybenzyl) -3- (2,4-dimethy1-phenyl) urea 94.6 10 1- (n-heptyl) -1- (4-butyloxybenzyl) -3- (2,4,5-trimethylf enyl) urea 95.6 1-benzyl-1- (4-butyloxybenzyl) -3- (2,4-dimethylphenyl) urea 91,7 1-benzyl-1- (4-butyloxybenzyl) -3- (2,4, 5-trimethyl-pheny1) urea 95.8 15 1- (9-octadecenyl) -1- (4-n-butylbenzyl) -3- (2,4-dimethyl-phenyl) urea 42.2 1-benzyl-1- (4-n-butylbenzyl) -3- (2,4,5-trimethyl-phenyl) urea. 90.5 1- (9-octadecenyl) -1- (4-n-butylbenzyl) -3- (2,4,5-tri-20-methylphenyl) urea 9.4 1-benzyl-1 [2-phenyl-1 - (4-benzyloxyphenyl) ethyl] - 3- (2,4,6-trimethylphenyl) urea 90.0 1- (n-heptyl) -1- (4-n-butoxybenzyl) -3- (2,4,6 -tri-chlorophenyl) urea 90.0 25 1- (n-heptyl) - (4-n-butoxybenzyl) -3- (2,4-dichlorophenyl) urea 79,9 1- (n-heptyl) -4 -n-butoxybenzyl) -3- (2-trifluoromethyl-4-chlorophenyl) urea 89,4 1-benzyl-1- (4-n-butoxybenzyl) -3- (2,4,6-trichlorophenyl) urea 95 .2 30 1-benzyl-1- (4-n-butoxybenzyl) -3- (2,4-dichlorophenyl) urea 80,0 1-benzyl-1- (4-n-butoxybenzyl) -3- (2-trifluoromethyl -4-chlorophenyl) urea 85.0 1- (n-heptyl) -1- (4-n-butoxybenzyl) -3- (3-trifluoromethyl-phenyl) urea 82.4 35 1- (n-benzyl-1- (4-n-butoxybenzyl) -3- (3-trifluoromethyl-phenyl) urea 87.0 1- (n-heptyl) -1- (4-n-butylbenzyl) -3- (2,4-dichlorophenyl) urea 80.0 1- (n-heptyl) -1- (4-n-butylbenzyl) -3- (2-trifluoro-40-methyl-4-chlorophenyl) urea 90.0 1- (n-heptyl) -1- ( 4-n-butylbenzyl) -3- (2,4,6-trichlorophenyl) urea 90.0 ........... 83 0 0 26 9 ........ "" ... .......

-19- 1- (n-heptyl) -1- (4-n-butylbenzyl) -3- (3-trifluoromethylphenyl) urea 85.0 1- (n-heptyl) -1- (4-n-butylbenzyl) ) -3- (2,4,5-trichlorophenyl) urea 46.5 5 1-benzy1-1- (4-n-butylbenzyl) -3- (2-methyl-4-chlorophenyl) urea 94, 3 1- (n-heptyl) -1- (4-n-butoxybenzyl) -3- (2,4-difluorophenyl) urea 82.7 1- (n-heptyl) -1- (4-n-butoxybenzyl) ) -3- (2-methy1-10 4-chloropheny1) urea 91.7 1- (n-heptyl) -1- (2-fury1) -3- (2,4,5-trimethylphenyl) urea 93.8 1 - (n-heptyl) -1- (2-fury1) -3- (2,4,6-trichlorophenyl) urea 96.1 1- (n-heptyl); -1- (4-n-butylbenzyl) -3- (2-methyl-4-chlorophenyl) urea 92,5 15 1- (n-heptyl) -1- (4-n-butylbenzyl) -3- (2, 4-difluorophenyl) urea 9010 1- (n-heptyl) -1- (4-n-butylbenzyl) -3- (4-carboethoxy-phenyl) urea 92.4 1- (n-heptyl) -1- ( 4-n-butylbenzyl) -3- (2-methylphenyl) urea 97.4 20 1- (n-heptyl) -1- (4-n-butylbenzyl) -3- (3-methylphenyl) urea 93.8 1- (n-heptyl) -1- (4-n-butylbenzyl) -3- (4-carboxyphenyl) urea 61,8 1- (n-heptyl) -1- (2-phenylethyl) -3- (2-methy 1 -4-chlorophenyl) urea 93.8 1- (n-heptyl) -1- (2-phenylethyl) -3- (2,4,5-trichloro-25-phenyl) urea 77.3 1- (n- heptyl) -1- (2-phenylethyl) -3- (2-trifluoromethyl-4-chlorophenyl) urea 88,3 1- (n-heptyl) -1- (2-phenylethyl) -3- (2,4-dimethylphenyl) ) urea 95.7 1- (n-heptyl) -1- (2-phenylethyl) -3- (2,4-dichlorophenyl) urea 91,8 30 l- (n-heptyl) -1- (2-phenylethyl) -3- (2,4-difluorophenyl) urea 94.1 1- (n-heptyl) -1- (2-phenylethyl) -3- (3-trifluoromethyl-phenyl) urea 88.4 1-benzy1-1- [2-phenyl-1- (4-benzyloxyphenyl) ethyl] -3- (2,4,6-trichlorophenyl) urea 95.0 35 1- (4-n-pentylbenzyl) -1- (4-n-pentyloxyben zyl) - 3- (2,4,6-trichlorophenyl) urea 95.5 1- (4-n-pentylbenzyl) -1- (4-n-pentyloxybenzyl) - 3- (2,4-dichlorophenyl) urea 85 .0 1- (4-n-pentylbenzyl) -1- (4-n-pentyloxybenzyl) -40 3- (2,4,5-trichlorophenyl) urea 80.0 1- (4-n-pentylbenzyl) -1- (4-n-pentyloxybenzyl) - 3- (2-trifluoromethyl-4-chlorophenyl) urea 81.0 8300269 -20- 1- (4-n-petttylbenzyl) -1- (4-n-pentyloxybenzy1) -3- ( 3-tri- 85.0 fluoromethylphenyl) urea 1- (4-n-pentylbenzyl) -1- (4-n-pentyloxybenzyl) -3- (2,4-difluorophenyl) urea 90.0 5 1- (4-n -pentylbenzyl) -1- (4-n-penty loxybenzyl) -3- (2-methyl-4-chlorophenyl) urea 91.0 1- (4-chlorobenzyl) -1- (1-naphthylmethyl) -3- (2 4,6-tri-chlorophenyl) urea 77.0 1- (4-chlorobenzyl) -1- (1-naphthylmethyl) -3- (2-methyl-ΙΟ 4-chlorophenyl) urea 94.0 1- (4- chlorobenzyl) -1- (1-naphthylmethyl) -3- (2,4-difluorophenyl) urea 84.0 1- (4-chlorobenzyl) -1- (1-naphthylmethyl) -3- (3-trifluoromethylphenyl ) urea 80.0 15 1- (4-chlorobenzyl) -1- (1-naphthylmethyl) -3- (2,4,5-trichlorophenyl) urea 86.0 1-benzy1-1- [2-pheny1- 1- (4-benzyloxyphenyl) ethyl] - 3- (2,4,5-tri chlorophenyl) urea 95.0 1-benzy1-1- (4-n-butyloxybenzyl) -3- (2,4,5-trichloro-20-phenyl) urea 89.0 1-benzy1-1- (2-pheny1-1 - (4-benzyloxyphenyl) ethyl] - 3- (2,4-difluorophenyl) urea 70.0 1-benzy1-1- (4-n-butoxybenzyl) -3- (2,4-difluorophenyl) urea 88, 0 25 1-benzy1-1- [2-pheny1-1- (4-benzyloxyphenyl) ethyl] - 3- (2,4-difluorophenyl) urea 91.0 1-benzy 1-1- [2-pheny 1-1 - (4-benzyloxyphenyl) ethyl] - 3- (2-trifluoromethyl-4-chlorophenyl) urea 92.0 1-benzy1-1- [2-pheny1-1- (4-benzyloxyphenyl) ethyl] -30 3- (3 -trifluoromethylphenyl) urea 74.0 1-benzy1-1- [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 35 1- (4-chlorobenzyl) -1- (1-naphthylmethyl) -3- (2-trifluoromethyl-1-) 4-chlorophenyl) urea 83.0

Inhibition of cholesterol absorption was assessed by feeding male Sprague-Dawley rats weighing 150-170 g for 2 weeks on a diet of 1% cholesterol: 0.5% 40 cholic acid. The diet also contained test compounds at a dose of 0.03% of the diet. Control rats were fed the same diet without an added compound. At the end of the test, the rats were killed by decapitation 8300269 -21-. Blood was collected, centrifuged at 1.5 kg times gravity for 10 minutes at 4 ° C, and then the serum was analyzed enzymatically for cholesterol and triglycerides according to the method of Trinder, P., Analyst, 77, 321 (1952). on a 5 Centrifichem 400 Analyzer. The livers were removed, a 0.4 g sample was taken from the center of the large lobe, and the sample was saponified using 25% 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 compound in inhibiting cholesterol absorption was measured by the decrease in serum cholesterol or liver cholesterol levels relative to the control rat values.

The results of this test for typical compounds of the invention are set forth in Table B below.

Table B

Compound Result 1-benzyl-1- (n-butyl) -3- (3-methyloxyphenyl) -3-phenylurea Active il-di- (n-butyl) -3- (2,4-dimethylphenyl) urea "20 1,1-di- (n-butyl) -3- (3,5-dimethylphenyl) urea "1.1-di- (n-butyl) -3- (2-methyl-3-chlorophenyl) urea" 1.1-di - (n-butyl) -3- (3,5-dichlorophenyl) urea "1,1-di- (n-butyl) -3- (4-n-butylphenyl) urea" 1,1-di- (n-hexyl) -3 - (2,4-dimethylphenyl) urea "1,1-di- (n-octyl) -3- (2,4-dimethylphenyl) urea" 1,1-di- (n-butyl) -3- (2-methylphenyl ) urea "1.1-di- (n-pentyl) -3- (2,4-dimethylphenyl) urea" 1,1-di- (n-decyl) -3- (2,4-dimethylphenyl) urea "1.1-di- ( isopentyl) -3- (2,4-dimethylphenyl) urea "1,1-di- (3,5,5-trimethylhexyl) -3- (2,4-dimethylphenyl) urea" 1,1-dibenzyl-3- (2 -methy1-5-chloropheny1) urea "1,1-dibenzyl-3- (2,4-dichlorophenyl) urea" 1,1-dibenzyl-3- (2-methyl 1-4-chlorophenyl) urea ”8300269 -22- 1.1- dibenzyl-3- (2,4-dimethylphenyl) urea Active 1.1-dibenzyl-3- (3-chloro-4-methylphenyi) urea "1,1-dibenzyl-3- (2-methoxy-5-methylphenyl) urea 11 1.1 - dibenzyl-3- ( 2,3-dimethylphenyl) urea · "5 1,1-dibenzyl-3- (3,4-dimethylphenyl) urea ·" 1,1-dibenzyl-3- (2,4,6-trimethylphenyl) urea "1,1-dibenzyl-3 - (4-n-butylphenyl) urea · "1.1-dibenzyl-3- (3-methylphenyl) thiourea ·" 1.1-dibenzy1-3- (4-phenoxyphenyl) urea · "10 1,1-dibenzy1-3- (3 -chloro-4-methylphenyl) thiourea · n 1,1-dibenzy1-3- (2,4-dmethylphenyl) thiourea · "1,1-dibenzyl-3- (2,4,5-trimethylphenyl) urea"

1.1-dibenzyl-3- (2-trifluoromethyl-4-chlorophenyl) urea M

1.1-dibenzy1-3- (3-bromophenyl) urea "- IS 1,1-dibenzyl-3- (2-trifluoromethylphenyl) urea ·" 1,1-dibenzyl-3- (4-carboethoxyphenyl) urea "1-benzyl-1- (n-butyl) -3- (2,4-dimethylphenyl) urea "1-benzyl-1- (n-butyl) -3- (2,6-dimethylphenyl) urea" 1-benzyl-1- (n-butyl ) -3- (3,5-dimethylphenyl) urea "1-benzyl-1- (1,2-diphenylethyl) -3- (2,4-dimethylphenyl) urea" 1- (2-fluorobenzyl) -1- ( 2-methoxybenzyl) -3- (2,4-dimethylphenyl) urea "1- (n-butyl) -1- (4-hexyloxybenzyl) -3- (2,4,6-trimethylphenyl) urea" 25 1- (n-butyl) -1- (4-heptyloxybenzyl) -3- (2,4,6-trimethylphenyl) urea "1-benzyl-1- (4-n-butylbenzyl) -3- (2,4-dimethylphenyl) urea "1-benzyl-1- (4-n-butylbenzyl) -3- (2,4,6-trimethylphenyl) urea" 1-benzyl-1- (4-n-butylbenzyl) -3- (4-n- butylphenyl) urea "30 1- (n-heptyl) -1- (4-n-butylbenzyl) -3- (2,4-dimethylphenyl) urea" 1- (n-heptyl) -1- (4-n- butylbenzyl) -3- (2,4,5-trimethyl-phenyl) urea n 1- (n-heptyl) -1- (4-butyloxybenzyl) -3- (2,4-dimethylphenyl) urea "35 1- ( n-heptyl) -1- (4-butyloxybenzyl) -3- (2,4,5-trimeth ylf enyl) urea "1-benzyl-1- (4-butyloxybenzyl) -3- (2,4-dimethylphenyl) urea" 8300269-23-1-benzyl-1- (4-butyloxybenzyl) -3- (2, 4,5-trimethylphenyl) - Active urea 1-benzyl-1- (4-n-butylbenzyl) -3- (2,4,5-trimethylphenyl) - urea "5 1-benzyl-1- [2-phenyl-1 - (4-benzyloxyphenyl) ethyl] -3- (2,4,6-trimethylphenyl) urea ”1- (n-heptyl) -1- (4-n-butoxybenzyl) -3- (2,4,6-trichloro - phenyl) urea "1- (n-heptyl) - (4-n-butoxybenzyl) -3- (2,4-dichlorophenyl) -10 urea" 1- (n-heptyl) - (4-n-butoxybenzyl) - 3- (2-trifluoromethyl) -4-chlorophenyl) urea "1-benzyl-1- (4-n-butoxybenzyl) -3- (2,4,6-trichlorophenyl) urea" 15 1-benzyl-1- ( 4-n-butoxybenzy1) -3- (2,4-dichlorophenyl) -urea "1-benzyl-1- (4-n-butoxybenzyl) -3- (2-trifluoromethyl- - 4-chlorophenyl) urea" 1 - (n-heptyl) -1- (4-n-butoxybenzyl) -3- (3-trifluoromethyl-20-phenyl) urea ”1- (n-heptyl) -1- (4-n-butoxybenzyl) -3- ( 2,4-dichlorophenyl) urea "1- (n-heptyl) -1- (4-n-butoxybenzyl) -3- (2-trifluoromethyl-4-chlorophenyl) urea" 25 1- (n-heptyl) -1 - (4-n-butoxybenzyl) -3- (2,4,6-trichlorophenyl) urea ”1-benzyl-1- (4-n-butylbenzyl) -3- (2-methyl-4-chlorophenyl) urea" 1- (n-heptyl) -1- (4-n-butoxybenzyl) -3- (2,4-difluorophenyl) -30 urea "1- (n-heptyl) -1- (4-n-butoxybenzyl) -3- (2-methyl-4-chloro-phenyl) urea" 1- (n-heptyl ) -1- (2-furyl) -3- (2,4,5-trimethylphenyl) urea "1- (n-heptyl) -1- (2-furyl) -3- (2,4,6-trichlorophenyl) urea "35 1- (n-heptyl) -1- @ n-buty Ibenzy 1) -3- (2-methyl-4-chlorophenyl) urea" 1- (n-heptyl) -1- (4-rt -butylb enzyl) -3- (2,4-difluorophenyl) urea "1- (n-heptyl) -1- (4-n-butylbenzyl) -3- (4-carboethoxyphenyl) urea" 40 1- (n -heptyl) -1- (4-n-butylbenzyl) -3- (2-methylphenyl) urea "1- (n-heptyl) -1- (4-n-butylbenzyl) -3- (3-methylphenyl) urea "¢ 300 269 ---------------- ------ V.

“* * -24- 1- (n-heptyl) -1- (2-phenylethyl) -2- (2-methyl-4-chloro-Active phenyl) urea 1- (n-heptyl) -1- (2- phenylethyl) -3- (2-trifluoromethyl-4-chlorophenyl) urea "5 1- (n-heptyl) -1- (2-phenylethyl) -3- (2,4-dimethyl-phenyl) urea" 1- (n -heptyl) -1- (2-phenylethyl) -3- (2,4-dichloropheny1) - urea "1- (n-heptyl) -1- (2-phenylethyl) -3- (2,4-dichluorophenyl) - 10 urea "1- (n-heptyl) -1- (2-phenylethyl) -3- (3-trifluoromethyl-phenyl) urea" 1-benzyl-1- [2-phenyl-1- (4-benzyloxyphenyl) ethyl] - 3- (2,4,6-trichlorophenyl) urea "15 1- (4-n-pentylbenzyl) -1- (4-n-pentyloxybenzy1) - 3- (2,4, β-trichlorophenyl) urea" 1- (4-n-pentylbenzyl) -1- (4-n-pentyloxybenzyl) - - · 3- (2,4-dichlorophenyl) urea “1- (4-n-pentylbenzyl) -1- (4-n-pentyloxybenzy1) -3-20 (2,4,5-trichlorophenyl) urea "1- (4-n-pentylbenzyl) -1- (4-n-pentyloxybenzyl) -3- (2,4-difluorophenyl) urea" 1- (4 -n-pentylbenzyl) -1- (4-n-pentyloxybenzyl) -3- (2-methyl-4-chlorophenyl) urea "25 1- (4-chlorobenzyl) -1- (1-naphthylmethyl) -3- (2 4,6-trichlorophenyl) urea "1- (4-chlorobenzyl) -1- (1-naphthylmethyl) -3- ( 2-methyl-4-chlorophenyl) urea "1- (4-chlorobenzyl) -1- (1-naphthylmethyl) -3-30 (2,4-difluorophenyl) urea" 1- (4-chlorobenzyl) -1- (1-naphthylmethyl) -3- (3-trifluoromethylphenyl) urea "1- (4-chlorobenzyl) -1- (1-naphthylmethyl) -3- (2,4,5-trichlorophenyl) urea" 35 1-benzyl-1 - (4-n-butyloxybenzyl) -3- (2,4,5-trichlorophenyl) urea "1-benzyl-1- [2-phenyl-1- (4-benzyloxyphenyl) -ethyl] - 3- (2.4 -difluorophenyl) urea "1-benzyl-1- (4-n-butoxybenzy1) -3- (2,4-difluoro-40-phenyl) urea, f 1-benzyl-1- (2-phenyl-1- (4- benzyloxyphenyl) ethyl] - 3- (2-trifluoromethyl-4-chlorophenyl) urea "1-benzyl-1- [2-phenyl-1- (4-benzyloxyphenyl) ethyl] -. - 3- (2-methyl-4-chlorophenyl) urea "45 1- (4-chlorobenzyl) -1- (1-naphthylmethyl) -3- (2,4-d-chlorophenyl enum" 8 3 0 0 2 6 9 - 25-

The tests shown in Tables A and B have actually been conducted and the results reported therein have actually been obtained or concluded from the tests.

Inhibition of cholesterol absorption was also assessed by feeding 5 male Sprague-Dawley rats weighing 150-170 g for two weeks on a diet of 1% cholesterol: 0/5% cholic acid. The diet also contained test compounds at doses of 0.01-0 / 1% of the diet. After the rats had been on the test diet for 9 days, each rat was tube-injected with a 14 wave-treated mixture of [4-C] cholesterol (6 Ci), 0.2 ml triolene, 10 mg cholic acid, 20 mg of cholesterol and 2 mg of the test compound in 0.8 ml of 10% non-fat dry milk.

Faeces were collected after each 24 hour period for the remaining 5 days during which the rats were kept on the diet of 1% cholesterol: 0.5% cholic acid plus test compound. Faecal C-neutral sterols were extracted with petroleum ether from saponified faeces by the method of Grundy, S. M. et al., J. Lipid Res., 6, 397, 1965) and counted in a scintillation counter. Acid sterols (bile acids) were extracted by acidifying the saponified faeces and extracting them in chloroform: methanol (2: 1) and counting the chloroform phase in a scintillation counter. Total extraction of the radioactivity (98-100%) from saponified faeces was accomplished by this procedure.

Liver and adrenal radioactivity was assessed by saponification and extraction in petroleum ether and counting by scintillation techniques. Total cholesterol in liver and adrenal glands was determined by the cholorimetric method of Zlatkis, A., et al., J. Lab. Clln. Med., 41, 486 (1953) to organic solvent-extracted saponified tissue, prepared by the method of Trinder, P., Analyst, 30 77, 321 (1952). Serum cholesterol and triglycerides were analyzed enzymatically by the method of Allain, C. C., et al., Clin. Chem. 20_ 14 470 (1974) with a centrifuge 400 Analyzer. Serum C cholesterol was determined by direct scintillation counting.

The effect of a test compound on cholesterol absorption was determined by: 14 1. increase in the secreted C-neutral sterol, 14 2. decrease in the secreted C-acid sterol, s 8300269 -26- 14 14 3. decrease in C- cholesterol or C-cholesterol in the liver, 14 14 4. decrease in C-cholesterol or C-cholesterol in the serum.

A compound was considered to effectively inhibit cholesterol absorption if it met at least the first two criteria.

The results of this test of typical compounds of the invention are shown in Table C below.

Table C

10 Compound Result 1-benzyl-1- (n-butyl) -3- (2,4-dimethylphenyl) urea Active 1,1-dibenzyl-3- (2,4-dimethylphenyl) urea "

The tests shown in Table C have actually been conducted and the results reported therein have actually been obtained or concluded from the tests.

When the compounds are used for the above mentioned application, they can be combined with one or more pharmaceutically acceptable carriers, for example, solvents, diluents, and the like, and can be administered orally in forms such as tablets, capsules, dispersible powders, granules suspensions containing, for example, about 0.5-5% suspending agents, syrups containing, for example, about 10-50% sugar, and elixirs containing, for example, about 20-50% ethanol, and the like are administered parenterally in the form of sterile injectable solutions or suspensions containing about 0.5-5% suspending agent in an isotonic medium. These pharmaceutical preparations may contain, for example, about 0.5 to about 90% of the active substance in combination with the carrier, more usually between 5 and 60% by weight.

The antiatherosclerotic effective dosage of the active ingredient used may vary depending on the particular compound used, the mode of administration, and the severity of the condition being treated. In general, however, satisfactory ..... 8 30 0 26 9 '-27 results are obtained when the compounds of the invention are administered in a daily dosage of about 2 mg to about 500 mg / kg body weight of the animal, at preferably administered in divided doses administered two to four times a day, or in the form of sustained-release preparations. For most large mammals, the total daily dose is from about 100 mg to about 5000 mg, preferably from about 100 mg to 2000 mg. Dosage forms suitable for internal use include about 25 mg to 500 mg of the active compound 10 in an intimate mixture with a solid or liquid pharmaceutically acceptable carrier. This dosing regimen can be adjusted to obtain the optimal therapeutic response. For example, several divided doses can be administered daily or the dose can be progressively reduced as the therapeutic situation requires. A pronounced practical advantage is that these active compounds can be administered orally as well as by intravenous, intramuscular or subcutaneous routes if necessary. Solid carriers include starch, lactose, dicalcium phosphate, microcrystalline cellulose, sucrose, and kaolin, while liquid carriers include sterile water, polyethylene glycols, nonionic surfactants, and edible oils such as corn oil, peanut oil, and sesame oil. depending on the nature of the active ingredient and the dosage form which is particularly desired.

It may be beneficial to include adjuvants commonly used in the preparation of pharmaceutical compositions such as flavoring agents, dyes, preservatives, and antioxidants, for example, vitamin A, ascorbic acid, BHT, and BHA.

From the viewpoint of ease of preparation and administration, solid preparations are preferred as pharmaceutical preparations, in particular tablets and hard-filled or liquid-filled capsules. Oral administration of the compounds is preferred.

These active compounds can also be administered parenterally or intraperitoneally. Solutions or suspensions of these active compounds as a free base or as a pharmacologically acceptable salt can be prepared in water, which is suitably mixed with a surfactant such as hydroxypropyl cellulose. Dispersions 8300269 t -28- can also be prepared in glycerol / liquid polyethylene glycols, and mixtures thereof in oils. Under normal conditions of storage and use, these compositions contain a preservative to prevent the growth of microorganisms.

The pharmaceutical forms suitable for injection include sterile aqueous solutions or dispersions and sterile powders for the unprepared preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and liquid to such an extent that easy handling with a syringe is possible. It must be stable under the conditions of preparation and storage and must be preserved against the contaminating action of micro-organisms such as bacteria and fungi.

The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (eg, glycerol, propylene glycol, and liquid polyethylene glycol), suitable mixtures thereof and vegetable oils.

The preparation of representative compounds of the invention is illustrated by the following specific examples.

Example I

1-Benzyl-1- (n-butyl) -3,3-diphenylurea

A solution of 20.0 g of phosgene in 100 ml of toluene was stirred at 0 ° C while a solution of 32.6 g of N-benzyl-n-butylamine in 50 ml of toluene was added over 15 minutes. The mixture was filtered and the filtrate was evaporated. The residue was distilled by evaporation at 105 ° C under reduced pressure (250-350 µm) to yield N-benzyl-N- (n-butyl) carbamyl chloride as a colorless liquid.

A solution of 3.89 g of diphenylamine in 25 ml of dimethylacet-30 amide was added over 1 hour to 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 at 45-50 ° C.

The mixture was stirred at 50 ° C for 2 hours and then poured into water. The mixture was extracted with methylene chloride, and the extract was evaporated. The residue was chromatographed using silica gel as adsorbent and acetone-hexane as eluent ------------ 8300 26 9 ....... - ........ ....- -29- purified. After evaporation of the eluent, the residue was distilled by evaporation at 165 ° C under reduced pressure (150 µm) to give 1-benzy1-1- (n-butyl) -3,3-diphenylurea as a viscous, clear, colorless liquid obtained.

Example IX

1-Benzyl-1- (n-butyl) -3- (3-chlorophenyl) -3-phenylurea

A solution of 5.09 g of N-phenyl-3-chloroaniline in 20 ml of toluene was added to a solution of 4.70 g of phosgene and 3.64 g of N, N-dimethylaniline in 55 ml of toluene and the mixture was adjusted to 40 ° C and then stirred while cooling to room temperature in 45 minutes. The mixture was extracted with water, and the organic layer was separated and evaporated to about half its volume. 100 ml of toluene were added to this solution, followed by 9.80 g of N-benzy 1-n-bufcylamine. The resulting mixture was refluxed for 30 minutes and then washed with water, 1N hydrochloric acid and saturated with sodium bicarbonate solution. The organic layer was separated, dried over sodium sulfate, decolorized with active charcoal, and evaporated. The residue was distilled by evaporation at 185-190 ° C under reduced pressure (105 µm) using 1-benzyl-1- (n-butyl) -3- (3-chlorophenyl) -3-phenylurea as a viscous, pale yellow liquid was obtained.

The compounds in Table D below were prepared from the corresponding amines using phosgene or thiophosgene according to the methods described in Examples I and II.

Table D

Example Compound Melting point III 1,3-dibenzyl-1- (n-buty1) -3-phenylurea yellow oil IV 1-benzyl-1- (n-buty1) -3- (2-naphthyl) -3-phenylurea orange oil V 1-benzy1-1- (n-butyl) -3- (3-methylphenyl) - 3-phenylurea oil 22 VI 1-benzyl-1- (n-butyl) -3- (4-isopropyl amber phenyl) -3 -phenylurea oil 830 0 269 ..........

«_ Yi -30- VII 1-benzyl-1- (n-butyl) -3- (3-amber methoxyphenyl) -3-phenylurea oil VIII 1-benzyl-1- (n-butyl) -3- (3- chlorophenyl) -3- (2-naphthyl) urea yellow oil 5 IX 1-benzyl-1- (n-butyl) -3- (1-naphthyl) - amber 3-phenylurea oil X 1-benzyl-1- ( n-butyl) -3,3-dibenzyl-urea yellow oil XI 1-benzy1-1- (n-butyl) -3,3-di (2-naphthyl) - amber 10 urea oil XII 1-Benzyl-1- ( n-butyl) -3-benzyl-3- (4-chlorophenyl) urea XIII 1-benzyl-1- (n-butyl) -3-benzyl-3-oil (2,4-dimethylphenyl) urea 15 XIV 1- benzyl-1- (n-butyl) -3-benzy1-3-oil 2,4-dichlorophenyl) urea XV 1-benzyl-1- (n-butyl) -3- (3-nitrobenzyQ-3- oil (3, 5-dimethoxyphenyl) urea XVI 1-benzyl-1 - (n-butyl) -3- (2,4-dimethylbenzyl} - ..

20 3- (2,4-diphenyl) urea ° 1 XVII 1-benzyl-1- (n-butyl) -3- (2,4-dichloro-oil benzyl) -3- (2,4-dichlorophenyl) urea XVIII 1-benzyl-1- (n-butyl) -3- (2-chlorobenzyl) oil 3- (2-chlorophenyl) urea 25 XIX 1-benzyl-1- (n-butyl) -3- (4-methylphenyl) ) - 3- (4-methylbenzyl) urea XX 1-benzyl-1- (n-butyl) -3- (2,4-dimethyl-1-benzyl) -3- (2,4-dichlorophenyl) urea XXI 1-benzyl -1- (n-butyl) -3- (2,4-dichloro-oil, benzyl) -3- (2,4-dimethylphenyl) urea XXII 1-benzyl-1- (n-butyl) -3- (3 -chloro-4- oil methylbenzyl) -3- (4-methylphenyl) urea XXIII 1-benzyl-1- (n-butyi) -3- (2,4-dimethyl-1-benzyl) -3-phenylurea XXIV 1 -benzyl-1- (n-butyl) -3- [3,5-di (trifluoromethyl) benzyl] -3-phenylurea

XXV 1-benzyl-1- (n-butyl) -3- (3-aminobenzyl) - i56-158eC

3- (3,5-dimethoxyphenyl) urea picrate XXVI 1-benzyl-1- (n-butyl) -3-benzy1-3- (3-amino-96-ggoc 40 phenyl) urea

XXVII 1-benzyl-1- (n-butyl) -3-benzy1-3- 63-69 ° C

(2,4,6-trimethylphenyl) urea XXVIII 1-benzyl-1- (n-butyl) -3-benzy1-3- -.

(3-nitrophenyl) urea yellow oil 45 XXIX 1-benzyl-1- (n-butyl) -3-benzy 1-3-.

(3-acetamidophenyl) urea oxie 8300269 * -31-

Example XXX

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 p-toluenesulfonic acid, and 150 ml of toluene 5 was stirred under reflux using a Dean-Stark water trap . Evaporation of the mixture gave a solid which was recrystallized from ethanol to give N- (2,4-dimethyl-benzylidene) -2,4-dichloroaniline, mp 102-106 ° C.

Anilines prepared by the method of Example XXX are listed in Table E below.

Table E

Example Compound Melting point XXXI N-benzylidene-2,4,6-trimethylaniline yellow oil

XXXII N-benzylidene-2,4-dichloroaniline 60-63 ° C

XXXIII N- (4-methylbenzylidene) -3-chloro-86-89 ° C 4-methylaniline XXXIV Ν'- (2,4-dimethylbenzylidene) -2,4-118-121 ° C dimethylaniline

XXXV N- (2,4-dichlorobenzylidene) -2.4-105-107 ° C

dimethylaniline

XXXVI N- (3-nitrobenzylidene) -3,5-dimethoxy- H3-H6 ° C

aniline

XXXVII N-benzylidene-4-chloroaniline 60-62 ° C

XXXVIII N-benzylidene-2,4-dimethylaniline oil

XXXIX N- (2,4-dichlorobenzilidene) -2.4-134-139 ° C

dichloroaniline XL N- (2-chlorobenzylidene) -2-chloro-

aniline 111-117 ° C

XLI N- (4-methylbenzylidene) -4-methyl-90-93 ° C

aniline XLII N-benzylidene-3,5-di (trifluoro- ...

methyl) aniline

XLIII N - (4-benzyloxybenzylidene) -4-carbo-140-142 ° C

Ethoxy aniline

XLIV N-benzylidene-3-nitroaniline 69-72 ° C

8300269 -32-

Example XLV

N- (2,4-dimethylbenzyl) -2,4-dlchloroaniline

A mixture of 13.9 g of N- (2,4-dimethylbenzylidene) -2,4-dichloroaniline, 1.89 g of sodium borohydride, and 150 ml of ethanol was stirred under reflux for 5 h, allowed to decant. cool, and poured into water. Recrystallization from ethanol gave N- (2,4-dimethylbenzyl) → 2,4-dichloroaniline, m.p. 88-90 ° C.

Anilines prepared by the method of Example XLV are listed in Table P below.

• V

Table F

Example Compound Melting point XLVI N-benzyl-2,4,6-trimethylaniline oil XLVII N-benzyl-2,4-dichloroaniline oil 15 XLVIII N- (4-methylbenzyl) -3-chloro-4-oil methylaniline XLIX - N- ( 2,4-dimethylbenzy1) -2,4-dimethylaniline L N- (2,4-dichlorobenzy1) -2,4- 70-72 ° C 20 dimethylaniline LI N- (3-nitrobenzyl) -3,5-dimethyloxy-amber aniline oil

Lil N-benzyl-4-chloroaniline 48-49 ° C

LUI N-benzyl-2,4-dimethyl laniline 28-33 ° C

LIV N- (2,4-dichlorobenzy1) -2.4- 84-86 ° C

dichloroaniline

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

LVI N- (4-methylbenzyl) -4-methylaniline 50-54 ° C

LVII N-benzyl-3,5-di (trifluoromethyl) oil 30 aniline LVIII N- (4-benzyloxybenzyl) -4-carbo-

ethoxyaniline 147-150 C

LIX N-benzyl-3-nitroaniline 106-108 ° C

............ 8 3 Ö 0 2 6 9 ..... .........................

-33-

Example LX

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

A solution of 4.89 g of 2,4-dimethylphenyl isocyanate in 100 ml of hexane was added to a solution of 4.41 g of N-benzyl-n-butyl-5 amine in 150 ml of hexane and the solution was stirred at room temperature for 2 hours and then evaporated. The residual solid was recrystallized from pentane to obtain 1-benzyl-1- (n-butyl) -3- (2,4-dimethylphenyl) urea, m.p. 70-71 ° C.

The compounds in Table G were prepared from the corresponding aryl isocyanates or aryl isothiocyanates and secondary amines according to the method of Example LX.

Table G

Example Compound Melting point (° C) 15 LXI 1-benzyl-1- (n-butyl) -3- (2-methyl-48-53 phenyl) urea LXII 1-benzyl-1- (n-butyl) -3- ( 3-methyl-Q. Q «, ^» \ «« - phenyl) urea LXIII 1-benzyl-1- (n-butyl) -3- (4-methyl- 102-103 phenyl) urea LXIV 1-benzyl- 1- (n-butyl) -3- (2,3-dimethyl- __ __

/ / - / O

phenyl) urea

LXV 1-benzyl-1- (n-butyl) -3- (2,5-dimethyl-OQ

f ».« o / ** oy phenyl) urea 25 LXVI 1-benzyl-l- (n-butyl) -3- (2,6-dimethyl-125-126 phenyl) urea LXV1I 1-benzyl-l- (n -butyl) -3- (3,4-dimethyl-Q.-phenyl) -urea LXVIII 1-benzyl-1- (n-butyl) -3- (3,5-dimethyl-. «A · * ** * 30 phenyl) urea LXIX 1-benzyl-1- (n-butyl) -3- (2,4,6-tri-141-144 methylphenyl) urea LXX 1-benzyl-1- (n-butyl) -3- (3,4,5-tri- ^ 44-1 ^ methoxyphenyl) urea 35 LXXI 1-benzyl-1- (n-butyl) -3- (3,4-di-102-105 chlorophenyl) urea LXXII 1- benzyl-1- (n-butyl) -3- (3,5-di-100-103 chlorophenyl) urea 8300269 -34- LXXIII 1-benzyl-1- (n-butyl) -3- (3-tri- 86 -87 fluoromethylphenyl) urea LXXIV 1-benzyl-1- (n-butyl) -3- (3-chloro-52-54 2-methoxyphenyl) urea 5 LXXV 1-benzyl-1- (n-butyl) -3- ( 5-chloro-61-63 4-methoxyphenyl) urea LXXVI 1-benzyl-1- (n-butyl) -3- (3-chloro.

4-methylphenyl) urea ge eo xe LXXVII 1-benzyl-1- (1,2-diphenylethyl) - 157-158 10 3- (2,4-dimethyl If enyl) urea LXXVIII l-benzyl-l - [- (3 -methoxyphenyl) -2-phenyl-124-126 ethyl] - 3 - (2,4-dimethylphenyl) urea LXXIX 1-benzyl-1- [1- (4-benzyloxyphenyl) -2-140-141 phenyl] -3- (2,4-dimethylphenyl) urea 15 LXXX 1-benzyl-1 - [- (3-methoxyphenyl) -2-phenyl-125-126 ethyl] -3- (3-trifluoromethylphenyl) urea LXXXI 1-benzyl-1- ( n-pentyl) -3- (2,4-dimethyl-phenyl) urea LXXXI I 1-benzyl-1- (n-hexyl) -3- (2,4-dimethyl- ^ 20 phenyl) urea LXXXI 11 1-benzyl -1- (n-octal) -3- (2,4-dimethyl- & phenyl) urea LXXXIV 1-benzyl-1- (n-undecyl) -3- (2,4-dimethyl-oil phenydiurea 25 LXXXV 1- benzyl-1- (n-butyl) -3- (3-phenyl) thio- 83-85 urea LXXXVI 1-benzyl-1- (n-butyl) -3- (3-chloro-52-54 2-methoxyphenyl) urea LXXXVII 1-benzyl-1- (n-butyl) -3- (5-chloro-161-163 30 2-methoxyphenyl) urea LXXXVIII 1- (n-butyl) -1- (2-fluorobenzyl) -3- 76 -77 (2,4-dimethylphenyl) urea LXXXIX 1- (n-butyl) -1- (4-fluorobenzyl) -3- 78-79 (2,4-dimethylphenyl) urea 35 XC 1- (n-butyl) -1- (2-chlorobenzyl) -3- 101-102 (2,4-dimethylphenyl) urea XCI 1- (n-butyl) -1- (2,6-dichlorobenzyl) - 3-145-146 (2.4 -dimethylphenyl) urea XCII 1- (4-bromobenzyl) -1- (n-butyl) - 61-63 40 3- (2,4-dimethylphenyl) urea XCIII 1- (n-butyl) -1- (4-n -butylbenzyl) - 60-62 3- (2,4-dimethylphenyl) urea XCIV 1- (n-butyl) -1- (4-methylbenzyl) -3- oil (2,4-dimethylphenyl) urea 830 0 269 .. ......... ................... ~ -35- XCV 1- (n-butyl) -1- (4-tert-butylbenzyl) - 28-31 3- (2,4-dimethylphenyl) urea XCVI 1- (n-butyl) -1- (4-chlorobenzyl) -3- oil (2,4-dimethylphenyl) urea 5 XCVII 1- (n-butyl ) -1- (4-methoxybenzyl) -oil 3- (2,4-dimethylphenyl) urea XCVIII 1- (n-butyl) -1- (3,4-methylenedioxybenzyl) -3- (2,4-dimethylphenyl ) urea XCIX 1- (n-butyl) -1- (4-trifluoromethyl-10-benzyl) -3- (2,4-dimethylphenyl) urea C 1- (n-butyl) -1- (4-phenylbenzyl) - 3-82-83 (2,4-dimethylphenyl) urea

Cl 1- (n-butyl) -1- (2-phenylethyl) -3- oil (2,4-dimethylphenyl) urea 15 CII 1- (n-butyl) -1- [2- (4-fluorophenyl) ethyl] - ^ 3- (2,4-dimethylphenyl) urea CIII 1- (n-butyl) -1- [2- (4-chlorophenyl) ethyl] - ^ 3- (2,4-dimethylphenyl) urea CIV 1- (n -butyl) -1- [2- (3-methoxyphenyl) ethyl] - 020 3- (2,4-dimethylphenyl) urea CV 1- (n-butyl) -1- (3-phenylpropyl) -3- oil ( 2,4-dimethylphenyl) urea CVI 1- (n-butyl) -1- [4- (n-pentyl) benzyl] - 65-67 3- (2,4-dimethylphenyl) urea CVII 1- (n-butyl ) -1- [4- (n-hexyl) benzyl] -3-oil (2,4-dimethylphenyl) urea CVIII 1- (n-butyl) -1- (3-chlorobenzyl) -3- oil (2,4 -dimethylphenyl) urea CIX 1- (n-butyl) -1- [4- (n-butoxy) benzyl] oil 30- (2,4-dimethylphenyl) urea CX 1- (n-butyl) -1- [ 4- (n-pentyloxy) benzyl] oil 3- (2 r4-dimethylphenyl) urea CXI 1- (n-butyl) -1- [4- (n-hexyloxy) benzyl] oil 3- (2,4- dimethylphenyl) urea CXII 1- (n-butyl) -1- [4- (n-heptyloxy) benzyl] oil 3- (2,4-dimethylphenyl) urea CXIII 1- (n-butyl) -1- (4 nitrobenzyl) -3- (2,4-oil dimethylphenyl) urea CXIV 1- (n-butyl) -1- [2- (2-methylphenyl) ethyl] - 102 -103 40 3- (2,4-dimethylphenyl) urea CXV 1- (n-butyl) -1- [2- (3-methylphenyl) ethyl] oil 3- (2,4-dimethylphenyl) urea CXVI 1- ( n-butyl) -1- [2- (4-methylphenyl) ethyl] - 3- (2,4-dimethylphenyl) urea 8300269 • * -36- CXVII 1- (n-butyl) -1- [2- ( 4-methoxyphenyl) ethyl] - 3- (2,4-dimethylphenyl) urea ° ie CXVIXI 1- (n-butyl) -1- [2- (3-fluorophenyl) ethyl] - 3- (2,4-dimethylphenyl) urea ° le 5 CXIX 1- (n-butyl) -1- [2- (2-chlorophenyl) ethyl] - 3- (2,4-dimethylphenyl) urea oe CXX 1- (n-butyl) -1- [2 - (3-chlorophenyl) ethyl] - 3- (2,4-dimethylphenyl) urea ° C 10 CXXI 1- (n-butyl) -1- [2- (3-bromophenyl) ethyl] - ..

3- (2,4-dimethylphenyl) upeum ° ie CXXII 1- (n-butyl) -1- [2- (3/4-methylenedioxyphenyl) ethyl] -3- (2,4-dimethylphenyl) urea ° ie CXXIII 1- (n-butyl) -1- (2-adamantylethyl) -3- 134-135 15 (2,4-dimethylphenyl) urea CXXIV 1- (n-butyl) -1- (α-cyclohexylbenzyl) -3 - 12-113 (2/4-dimethylphenyl) urea CXXV 1- (n-butyl) -1- (di- (4-chlorophenyl) methyl) -. , 3- (2,4-dimethylphenyl) urea 145-147 20 CXXVI 1- (n-butyl) -1- (3,4-dichlorobenzyl) -3- (2/4-dimethylphenyl) urea 120-121 CXXVII 1- (n-butyl) -1- (3-trifluoromethylbenzyl) - 1- (4-fluorobenzyl) -3- (2,4-dimethylphenyl) - 114-115 urea 25, CXXVIII 1- (4-chlorobenzyl) -1 - (1-naphthylmethyl-.

3- (2,4-dimethylphenyl) urea CXXIX 1- (4-methoxybenzyl) -1- (2/4-dichloro ^ 4 ^ 26 benzyl) -3- (2,4-dimethylphenyl) urea CXXX 1- (3 -chlorobenzyl) -1- (4-methoxybenzyl) - ins-109 30 3- (2,4-dimethylphenyl) urea CXXXI 1- (4-phenylbenzyl) -1- (3,4-dichloro-103-105 benzyl) - 3- (2,4-dimethylphenyl) urea CXXXII 1- (4-fluorobenzyl) -1- (4-methylbenzyl) - 100-130 3- (2/4-dimethylphenyl) urea 35 CXXXIII 1- (4-chlorobenzyl) - 1- (3/4-dimethoxy- 94-96 benzyl) -3- (2,4-dimethylphenyl) urea CXXXIV 1- (4-fluorobenzyl) -1- (3,4-methylene-122-124 dioxybenzyl) -3 - (2,4-dimethylphenyl) urea CXXXV 1- (n-butyl) -1- (4-methylthiobenzyl) - ^ 40 3— (2,4-dimethylphenyl) urea CXXXVI 1- (2,4-dichlorobenzyl) -1 - (4-methylthio-. ".

benzyl) -3- (2,4-dimethylphenyl) urea CXXXVII 1- [2- (3/4-dimethoxyphenyl) ethyl] - 1- (3,4-methylenedioxybenzyl) -3- oil 45 (2,4-dimethylphenyl) urea ............. 8 3 0 0 2 6 9 "" ...........

»-37- CXXXVIII 1- [2- (2-methylphenyl) ethyl] -1- (2,4-di-120-122 chlorobenzyl) -3- (2,4-dimethylphenyl) urea CXXXIX 1- [2- ( 4-methylphenyl) ethyl] -1- (4-chlorobenzyl benzyl) -3- (2,4-dimethylphenyl) urea 5 CXL 1- [2- (4-ethoxyphenyl) ethyl] -1- (2-chloro ~ Oil benzyl) -3- (2,4-dimethylphenyl) urea CXLI 1- [2- (3-fluorophenyl) ethyl] -1- (3-methoxy-94-95 benzyl) -3- (2,4-dimethylphenyl) urea CXLII 1- [2- (3-methoxyphenyl) ethyl] -1- (2-chloro-73-74 benzyl) -3- (2,4-dimethylphenyl) urea 10 CXLIII 1- (3,3-diphenylpropyl) - 1- (4-Fluorobenzyl) -1ng_i1n 3- (2,4-dimethylphenyl) urea CXLIV 1- (n-butyl) -1- (3,3-diphenylpropyl) -3- 94-95 (2,4-dimethylphenyl ) urea CXLV 1- (n-butyl) -1- (4-cyclohexylbutyl) oil 15 3- (2,4-dimethylphenyl) urea CXLVI 1- [2- (3,4-dimethoxyphenyl) ethyl] -1- ( 3-chloro-4-methylbenzyl) -3- (2,4-dimethyl-gum phenyl) urea CXLVII 1- [2- (2-methylphenyl) ethyl] -1- (4-bromo 126-127 benzyl) - 3- (2,4-dimethylphenyl) urea CXLVIII 1- [2- (3-trifluoromethylphenyl) ethyl] - 1- (2-chlorobenzyl) -3- (2> 4-dimethyl- 115-117 phenyl) urea CXLIX 1- (2-fluorobenzyl) -1- (2-methoxybenzyl) - 96-98 25 3- (2,4-dimethylphenyl) urea CL 1- [2- (3,4-dimethoxyphenyl) ethyl] -1- (4 -fluorobenzyl) -3- (2,4-dimethylphenyl) -gum urea CLI 1-f2- (4-ethoxyphenyl) ethyl] -1- (2,4-dimethylbenzy 1) -3- (2,4- dimethylphenyl) urea ^ ° m CLII 1- [2- (3-methylphenyl) ethyl] -1- (3-nitro-99-101 benzyl) -3- (2,4-dimethylphenyl) urea CLIII 1- [2- ( 2,5-dimethoxyphenyl) ethyl] -1- (3-chlorobenzyl) -3- (2,4-dimethylphenyl) - 86-88-35 urea CLIV 1- (n-butyl) -1- (2-methyl-2 , 2-diphenyl) - 159-160 ethyl-3- (2,4-dimethylphenyl) urea CLV 1- (n-butyl) -1- (4-hexyloxybenzyl) -3- 90-91 (2,4,6- trimethylpheny1) urea 40 CLVI 1- (n-butyl) -1- (4-heptyloxybenzyl) -3- (2,4,6-trimethylphenyl) urea CLVII 1- (n-butyl) -1-benzy1-3- ( 4-trifluoroacetyl-amino-3,5-dichlorophenyl) urea 83 0 0 26 9 ..........

-38- CLVIII 1-benzyl-1- (4-n-butybenzyl) -3- ..

(2,4-dimethylphenyl) urea. ° e CLIX 1-benzyl-1- (4-n-butylbenzyl) -3- oil (2,4,6-trimethylphenyl) urea 5 CLX 1-benzyl-1- (4-n-butylbenzyl) -3- (4 -n-butylphenyl) urea given no XT 1-benzyl-1- (4-n-butybenzyl) -3- 79-80 (4-n-phenoxypheny 1) urea CLXII 1- (n-heptyl) -1- (4-n-butylbenzyl) -,.

10 3- (2,4-dimethylphenyl) urea g CLXIII 1- (n-heptyl) -1- (4-n-butylbenzyl) - 3- (2,4,5-trimethylphenyl) urea g CLXIV 1-benzyl-1 - [2-pheny1-1- (4-benzyloxy-phenyl) ethyl] -3- (2,4,5-trimethylphenyl) - 157-158 urea CLXV 1- (n-heptyl) -1- (4-butyloxybenzyl ) - lie 3- (2,4-dimethylphenyl) urea ... .

CLXVI 1- (n-heptyl) -1- (4-butyloxybenzyl) -, oil 3- (2,4,5-trimethylphenyl) urea 9 20 CLXVII 1-benzyl-1- (4-butyloxybenzyl) - solid 3- ( 2,4-dimethylphenyl) urea CLXVIII 1-benzyl-1- (4-butyloxybenzyl) - solid 3- (2,4,5-trimethylphenyl) urea CLXIX 1- (9-octadecenyl) -1- (4-n-butylbenzyl) ) -.

25 3- (2,4-dimethylphenyl) urea g CLXX 1-benzyl-1- (4-n-butylbenzyl) -3- le Qlie (2,4,5-trimethylphenyl) urea y CLXXI 1- (9-octadecenyl) -1- (4-n-butylbenzyl) -1Q oil 3- (2,4,5-trimethylphenyl) urea CLXXII 1-benzyl-1- [2-phenyl-1- (4-benzyloxy-phenyl) ethyl] -3- (2,4,6-trimethy1-140-141 phenyl) urea CLXXIII 1- (n-heptyl) -1- (4-n-butoxybenzyl) - 63-64 3- (2,4,6-trichlorophenyl ) urea 35 CLXXIV 1- (n-heptyl) - (4-n-butoxybenzyl) - m 3- (2,4-dichlorophenyl) urea CLXXV 1- (n-heptyl) - (4-n-butoxybenzyl) - 3- (2-triflxioromethyl-4-chlorophenyl) - 9 ° m urea 40 CLXXVI 1-benzyl-1- (4-n-butoxybenzyl) - 91-93 3- (2,4,6-trichlorophenyl) urea CLXXVII 1-benzyl -1- (4-n-butoxybenzyl) - ^ 3- (2,4-dichlorophenyl) urea .................. 83 0 0 26 r ..... .. ~ ...................... '~ ft -39- CLXXVIII 1-benzyl-ί- (4-n-butoxybenzyl) -3- ^ ( 2-trifluoromethyl-4-chlorophenyl) urea CLXXIX 1- (n-heptyl) -1- (4-n-butoxybenzyl) -3- t (3-trifluoromethylphenyl) urea 5 CLXXX 1- (n-benzyl) - 1- (4-n-butoxybenzyl) -3- (3-trifluoromethylphenyl) urea 90 CLXXXI 1- (n- heptyl) -1- (4-n-butylbenzyl) -3- m (2,4-dichlorophenyl) urea 9 CLXXXI1 1- (n-heptyl) -1- (4-n-butylbenzyl) -3- 10 (2- trifluoromethyl-4-chlorophenyl) urea 90 CLXXXIII 1- (n-heptyl) -1- (4-n-butylbenzyl) -3- m (2,4,6-trichlorophenyl) urea CLXXXIV 1- (n-heptyl) -1 - (4-n-butylbenzyl) - 3- (3-trifluoromethylphenyl) urea 15 CLXXXV 1- (n-heptyl) -1- (4-n-butylbenzyl) - ^ 3- (2,4,5-trichlorophenyl) urea CLXXXVI 1-benzyl-1- (4-n-butylbenzyl) -3- 107-108 (2-methyl-4-chlorophenyl) urea CLXXXVII 1- (n-heptyl) -1- (4-n-butoxybenzyl) - 20 3- (2,4-difluorophenyl) urea CLXXXVIII 1- (n-heptyl) -1- (4-n-butoxybenzyl) - 3- (2-methyl-4-chlorophenyl) urea CLXXXIX 1- (n-heptyl) - 1- (2-fury1) -3- (2,4,5- 65-67 trimethylphenyl) urea CXC 1- (n-heptyl) -1- (2-furyl) -3- (2,4,6-. ..

trichlorophenyl) urea 9

CXCI 1 - (n-heptyl) -1- (4-n-butylbenzyl) -3- Q

(2-methyl-4-chlorophenyl) urea CXCII 1- (n-heptyl) -1- (4-n-butylbenzyl) -3- oil 30 (2-difluorophenyl) urea CXCIII 1- (n-heptyl) -1- (4-n-butylbenzyl) -3- 65-66 (4-carboethoxyphenyl) urea CXCXV 1- (n-heptyl) -1- (4-n-butylbenzyl) - ^ 3- (2-methylphenyl) urea 35 CXCV 1 - (n-heptyl) -1- (4-n-butylbenzyl) - oil 3- (3-methylpheny1) urea CXCVI 1- (n-heptyl) -1- (4-n-butylbenzyl) - 147-149> 3 - (4-carboxyphenyl) urea CXCVII 1- (n-heptyl) -1- (2-phenylethyl) - m 40 3- (2-methyl-4-chlorophenyl) urea 90 CXCVIII 1- (n-heptyl) -1- (2-phenylethyl) -m 3- (2,4,5-trichlorophenyl) urea CXCIX 1- (n-heptyl) -1- (2-phenylethyl) -. . . 3- (2-trifluoromethyl-4-chlorophenyl) - 90 45 urea ~ .......... 83 0 0 2 6 9 -40- CC 1- (heptyl) -! - (2-phenylethyl) - m 3- (2,4-dimethylphenyl) urea CCI 1- (n-heptyl) -1- (2-phenylethyl) uncle 3- (2,4-dichlorophenyl) urea 5 CCII 1- (n-heptyl) -1 - (2-phenylethyl) - 3- (2,4-difluorophenyl) urea ^ om CCIII 1- (n-heptyl) -1- (2-phenylethyl) - 3- (3-trifluoromethylphenyl) urea CCIV 1-benzyl-1 - [2-phenyl-1- (4-benzyl-131-133-oxyphenyl) ethyl] -3- (2,4,6-trichlorophenyl) urea CCV 1- (4-n-pentylbenzyl) -1- ( 4-n-penty1-oxybenzyl) -3- (2,4,6-trichloro-oil phenyl) urea 15 CCVI 1- (4-n-pentylbenzyl) -1- (4-n-pentyloxybenzyl) -3- (2,4-dichlorophenyl) oil urea CCVXI 1- (4-n-pentylbenzyl) -1- (4-n-penty1-oxybenzyl) -3- (2,4,5-trichloro-oil 20 phenyl) urea CCVIII 1- (4-n-pentylbenzyl) -1- (4-n-penty1-oxybenzyl) -3- (2-trifluoromethyl-4-oil chlorophenyl) urea CCIX 1- (4-n-pentyIbenzy1) -1- (4 -n-penty1- oxybenzyl) -3- (3-trifluoromethylphenyl) - oil urea CCX 1- (4-n-pentylbenzyl) -1- (4-n-penty1-. ol ^ oxybenzyl) -3- (2 , 4-difluorophenyl) urea CCXI 1- ( 4-n-pentylbenzyl) -1- (4-n-penty1-30 oxybenzyl) -3- (2-methyl-4-chlorophenyl) - oil urea CCXII 1- (4-chlorobenzyl-1- (1-naphthylmethyl) - 157-159 3- (2,4,6-trichlorophenyl) urea CCXIII 1- (4-chlorobenzyl) -1- (1-naphthylmethyl) - 168-169 35 3- (2-methyl-4-chlorophenyl) urea CCXIV 1 - (4-chlorobenzyl) -1- (1-naphthylmethyl) - 122-124 3- (2,4-difluorophenyreum CCXV 1- (4-chlorobenzyl) -1- (1-naphthylmethyl) - 127-129 3- (3-trifluoromethylphenyl) urea 40 CCXVI 1- (4-chlorobenzyl) -1- (1-naphthylmethyl) -no_H3 3- (2,4,5-trichlorophenyl) urea CCXVII 1-benzyl-1- [2-phenyl-1 - (4-benzyloxy-phenyl) ethyl] -3- (2,4,5-trichlorophenyl) - 142-145 urea 45 CCXVIII 1-benzyl-1- (4-n-butyloxybenzyl) -3- oil (2.4 .5-trichlorophenyl) urea 8 3 0 0 2 6 9 - a, ^ ft ft “-41- CCXIX 1-benzyl-1- [2-phenyl-1- (4-benzyloxy- 84-85 phenyl) ethyl] - 3- (2,4-difluorophenyl) urea CCXX 1-benzyl-1- (4-n-butoxybenzyl) -3- oil (2,4-difluorophenyl) urea 5 CCXXI 1-benzyl-1- [2-phenyl-1 - (4-benzyloxy-126-128 phenyl) ethyl] -3- (2,4-difluorophenyl) urea CCXXII 1-benzyl-1- [2-phenyl-1- (4-ben zyloxyphenyl) ethyl] -3- (2-trifluoromethyl-4- 99-101 chlorophenyl) urea CCXXIII 1-benzyl-1- [2-phenyl-1- (4-benzyloxyphenyl) ethyl] -3- ( 3-trifluoromethyl-102-104 phenyl) urea CCXXIV 1-benzyl-1- [2-phenyl-1- (4-benzyloxyphenyl) ethyl] -3- (2-methyl-4-chloro 125-126 phenyl) ) urea CCXXV 1- (4-chlorobenzyl) -1- (1-nafty Imethy 1) - 3- (2,4-dichlorophenyl) urea CCXXVI 1- (4-chlorobenzyl) -1- (1-nafty Imethy1) - 3 - (2-trifluoromethyl-4-chlorophenyl) - yellow glass 20 urea

Example CCXXVII

1-Benzyl-1- (n-butyl) -3- (3-chlorophenyl) urea

A solution of 1.56 g of phenyl chloroformate in 50 ml of ether was added dropwise to a stirred solution of 2.55 g of 25-chloroaniline in 35 ml of ether. The mixture was stirred at room temperature for 1 hour and then filtered. The filtrate was evaporated and the residue was crystallized from hexane to obtain phenytN- (3-chlorophenyl) carbamate.

A solution of 1.46 g of phenyl N- (3-chlorophenyl) carbamate in 15 ml of tetrahydrofuran was added to a solution of 1.92 g of N-benzyl-n-butylamine in 20 ml of tetrahydrofuran and the mixture was left under 24 hours reflux stirred boiling. The mixture was diluted with hexane and the precipitate was collected by filtration. Recrystallization from pentane gave 1-benzyl-1- (n-butyl) -3- (3-chlorophenyl) -35 urea, mp 69-70 ° C.

Example CCXXVIII

1- (Benzyl-1- (n-butyl) -3- (4-carboxyphenyl) urea

A solution of 5.30 g of 1-benzyl-1- (n-butyl) -3- (4-carboethoxyphenyl) urea in 100 ml of ethanol was treated with 25 ml of IN aqueous 8300 269 ........ ................ - sodium hydroxide, stirred under reflux for 16 hours, allowed to cool ora, acidified with 1N hydrochloric acid and filtered. The solid was recrystallized from ethanol to give 1-benzyl-1- (n-butyl) -3- (4-carboxyphenyl) urea as a white solid.

Example CCXXIX

1-Benzyl-1- (n-butyl) -3- (2-hydroxy-3-chlorophenyl) uceum

A solution of 1.73 g of 1-benzyl-1- (n-butyl) -3- (2-methoxy-3-chlorophenyl) urea and 1.00 ml of boron tribromide in 40 ml of methylene-10 chloride was stirred at room temperature for 3 days stirred and diluted with water * The organic layer was separated, dried and evaporated. The residue was crystallized from hexane to obtain 1-benzyl-1- (n-butyl) -3- (2-hydroxy-3-chlorophenyl) urea, mp 59-62 ° C.

15 Example CCXXX

N- (2-Chlorobenzyl) -3-methoxyphenylacetamide

A mixture of 12.5 g of 3-methoxyphenylacetic acid, 21.2 g of 2-chlorobenzylamine, 15.1 g of triethylamine, 19.3 ml of boron trifluoride etherate, and 500 ml of toluene was stirred under reflux for 18 hours using of a Dean-Stark water catcher and given the opportunity to cool down. The mixture was extracted with aqueous sodium hydroxide, dilute hydrochloric acid and water. The residual organic solution was then evaporated and the residue was crystallized from hexane to give N- (2-chlorobenzyl) -3-methoxyphenyl-25-acetamide as a yellow solid with a. melting point of 89-91 ° C was obtained.

Example CCXXXI

N- (n-butyl) -2-chlorobenzylamine

A solution of 21.2 g of N- (n-butyl) -2-chlorobenzamide in 100 ml of tetrahydrofuran was added with cooling to 200 ml of 1M

borane in tetrahydrofuran, and the mixture was stirred under reflux for 18 hours, allowed to cool and treated with 6N hydrochloric acid. The organic solvent was evaporated, and the residue was partitioned between ether and aqueous sodium hydroxide solution. The ether layer was separated, dried and evaporated. The residue was distilled to give N- (n-butyl) -2-chlorobenzylamine as a colorless liquid with a boiling point of 65-75 ° C at 60 ...

8300269 * m 1.- '' * -43-

Example CCXXXII

1,1-Dibenzyl-3- (2,4-dimethylphenyl) urea

A solution of 4.89 g of 2,4-dimethylphenyl isocyanate in 100 ml of hexane was added to a solution of 5.32 g of dibenzylamine in 150 ml of hexane, and the solution was added. it was stirred for 2 hours at room temperature and then evaporated. The residual solid was recrystallized from pentane to obtain 1,1-dibenzyl-3- (2,4-dimethylphenyl) -urea, m.p. 124-126 ° C.

The urea and thiourea compounds shown in Table H were prepared from the corresponding aryl isocyanates or aryl isothiocyanates and secondary amines according to the method of Example 1x, or were obtained commercially.

Table H

Example Compound Melting point C ° C) 15 CCXXXII! 1,1-dibenzyl-3- (2-methylphenyl) urea white solid CCXXXIV 1,1-dibenzyl-3- (3-methylphenyl) urea 126-128 CCXXXV 1,1-dibenzyl-3- (4-methylphenyl) urea 170-172 CCXXXVI 1,1-dibenzyl-3- (4-n-butylphenyl) urea 104-106 CCXXXVII 1,1-dibenzyl-3- (2,3-dimethylphenyl) urea white solid 20 CCXXXVIII 1,1-dibenzyl -3- (2,5-dimethylphenyl) urea "" "CCXXXIX 1,1-dibenzyl-3- (2,6-dimethylphenyl) urea" M "CCXL 1,1-dibenzyl-3- (3,4-dimethylphenyl) urea "" "CCXLI 1,1-dibenzyl-3- (3,5-dimethylphenyl) urea yellow solid CCXLII 1,1-dibenzyl-3- (2,4,5-trimethyl-141-147 phenyl) urea CCXLIII 1,1-dibenzyl-3- (2,4,6-trimethyl-, phenyl) urea CCXLIV 1,1-dibenzyl-3- (4-methoxyphenyl) urea cream colored solid CCXLV 1,1-dibenzyl-3- (4-n-butoxypheny1) urea 119-120 30 CCXLVI 1,1-dibenzyl-3- (4-methylthiophenyl) urea 196-198 CCXLVII 1,1-dibenzy1-3- (2-chlorophenyl) urea white solid CCXLVIII 1 , 1-dibenzyl-3- (3-chlorophenyl) urea "" "CCXLIX 1,1-dibenzyl-3- (4-chlorophenyl) urea" "" CCL 1,1-dibenzyl-3- (2-bromophenyl) u rheum 118-119 8300269 -44- CCLI 1,1-dibenzyl-3- (4-bromophenyl) urea white solid CCLII 1,1-dibenzyl-3- (4-iodophenyl) urea 233-235 CCLIII 1,1-dibenzyl -3- (2,3-dichlorophenyl) - white solid urea 5 CCLIV 1,1-dibenzyl-3- (2,4-dichlorophenyl) - „„ „urea CCLV 1,1-dibenzyl-3- (2,5 -dichlorophenyl) - „„ „urea CCLVI 1,1-dibenzyl-3- (3,5-dichlorophenyl) - 144-145 10 urea CCLVII 1,1-dibenzyl-3- (3-trifluoromethyl-1-cream phenyl) urea solid CCLVIII 1,1-dibenzyl-3- (3-acetylphenyl) urea 124-127 CCLIX 1,1-dibenzyl-3- (4-carboethoxy-91-93 phenyl) urea CCLX 1,1-dibenzyl-3- (4-phenoxyphenyl) urea 144-146.

CCLXI 1,1-dibenzyl— 3- (3-chloro-2-methyl-139-13-9 phenyl) urea CCLXII 1,1-dibenzyl-3- (3-chloro-4-methyl-white solid 20 phenyl) urea CCLXIII 1,1-dibenzyl-3- (4-chloro-3-trifluoro-146-148 methylphenyl) urea CCLXIV 1,1-dibenzyl-3- (4-chloro-2-trifluoro-82-83 methylpheny1) urea CCLXV 1,1-dibenzyl-3- (3-methylphenyl) thiourea 95-96 CCLXVI 1,1-dibenzyl-3- (2,3-dibenzophenyl) urea white solid CCLXVII 1,1-dibenzyl-3- (5-chloro -2-methyl- "" "phenyl) urea CCLXVIII 1,1-dibenzyl-3- (3-methoxyphenyl) urea" "" 30 CCLXIX 1,1-dibenzyl-3- (2-methoxyphenyl) urea cream-colored solid CCLXX 1,1-dibenzyl-3- (3-nitrophenyl) urea yellow solid CCLXXI 1,1-dibenzyl-3- (2,5-dimethoxyphenyl) - cream colored urea solid CCLXXII 1,1-dibenzy1-3- (2,6-dichlorophenyl) urea white solid 35 CCLXXIII 1,1-dibenzyl-3- (3,4-dichlorophenyl) urea "" "CCLXX IV 1,1-dibenzyl-3- (4-chloro-2-methyl - „„ „phenyl) urea CCLXXV 1,1-dibenzyl-3- (2-methoxy-5-methyl- ,,„ „phenyl) urea 40 CCLXXVI 1,1-dibenzyl-3- (6-chloro-2 -methylphenyl) - „„ „urea 8300269 -45- CCLXXVII 1,1-dibenzyl-3- (6-ethyl-2-methyl-fatty solid phenyl) urea CCLXXVIII 1,1-dibenzyl-3- (2,6- diethylphenyl) - „„ „urea 5 CCLXXIX 1,1-dibenzyl-3- (2,6-diisopropyl-„ „„ phenyl) urea CCLXXX 1, 1-dibenzyl-3- (4-nitrophenyl) urea yellow solid CCLXXXI 1 1,1-dibenzyl-3- (4-ethoxyphenyl) urea 129-130 10 CCLXXXII 1,1-dibenzyl-3- (2,5-difluorophenyl) - 67-68 urea CCLXXXIII 1,1-dlbenzyl-3- (2, 4-dibromophenyl) - 107-108 urea CCLXXXIV 1,1-dibenzyl-3- (3-chloro-4-methyl-109-110 15 phenyl) thiourea CCLXXXV 1,1-dibenzyl-3- (2,4-dimethylphenyl) - 159-161 thiourea CCLXXXVI. 1,1-dibenzyl-3- (3-trifluoromethyl-107-108 phenyl) thiourea 20 CCLXXXVTI 1,1-dibenzyl-3- (4-carboethoxy-108-110 phenyl) thiourea CCLXXXVIII 1,1-dibenzyl-3- ( 3,4-dibenzopheny1) urea 170-172 CCLXXXIX 1,1-dibenzyl-3- (2-trifluoromethyl-phenyl) -urea 25 CCXC 1,1-dibenzyl-3- (4-methylphenyl) urea white solid CCXCI 1,1-dibenzyl-3-phenylurea "" "

Example CCXCI1 1,1-Dibenzyl-3- (3-bromophenyl) urea

A solution of 1.56 g of phenyl chloroformate in 50 ml of ether 30 was added dropwise to a stirred solution of 3.44 g of 3-bromoaniline in 35 ml of ether, the mixture was stirred at room temperature for 1 hour and then filtered. The filtrate was evaporated , and the residue was crystallized from hexane to obtain phenyl N- (3-bromophenyl) carbamate, mp 89-90 ° C.

A solution of 1.46 g of phenyl N- (3-bromophenylcarbamate in 15 ml of tetrahydrofuran was added to a solution of 2.32 g of dibenzylamine in 20 ml of tetrahydrofuran and the mixture was diluted with hexane and the precipitate collected by filtration. Recrystallization -40 from pentane gave 1,1-dibenzyl-3- (3-bromophenyl) urea m.p. 102-103 ° C.

8300269 II i

W.

-46-

Example CCXCIII

1.1- Dibenzyl-3- (4-carboxyphenyl) urea

A solution of 5.61 g of 1,1-dibenzyl-3- (4-carboethoxyphenyl) urea in 100 ml of ethanol was treated with 25 ml of 1N aqueous sodium 5 hydroxide solution, stirred under reflux for 16 hours, allowing given to cool, acidified with 1N hydrochloric acid, and filtered. The solid was crystallized from ethanol to give 1,1-dibenzyl-3- (4-carboxyphenyl) urea as a white solid of 210-214 ° C.

10 Example CCXCIV

1-Benzyl-1- (n-butyl) -3- (phenyl) urea

A solution of 4.89 g of phenyl isocyanate in 100 ml of hexane was added to a solution of 4.41 g of N-benzyl-n-butylamine in 150 ml of hexane, and the solution was stirred at room temperature for 2 hours and then evaporated. The residual solid was recrystallized from pentane to obtain 1-benzyl-1- (n-butyl) -3- (phenyl) urea.

Example CCXCV

1.1- Di- (n-butyl) -3- (2,4-dimethylphenyl) urea. A solution of 4.89 g of 2,4-dimethylphenyl isocyanate in 100 ml of hexane was added to a solution of 3.48 g of di ( n-butyl) amine in 150 ml hexane, and the solution was stirred at room temperature for 2 hours and then evaporated. The residual solid was recrystallized from pentane to give 1,1-di- (n-butyl) -3- (2,4-dimethyl-phenyl) urea, mp 48-50 ° C.

The urea and thiourea compounds shown in Table I were prepared from the corresponding aryl isocyanates or aryl isothiocyanates and secondary amines according to the method of Example LX, or were obtained commercially.

83 0 0 2 6 9 · .....

-47-

Table I

Example Compound Melting point (° C) CCXCVI 1,1-di- (n-butyl) -3- (2-methylphenyl) urea 5 CCXCVn 1,1-di- (n-butyl) -3- (3-methylphenyl) - white solids urea CCXCVIII 1,1-di- (n-butyl) -3- (4-methylphenyl) - 90-91 urea CCXCIX 1,1-dHn-butyl) -3- (4- isopropylphenyl) - 60-61 5 10 urea CCC 1,1-di- (n-butyl) -3- (4-n-butylphenyl) - 44-46 urea CCCI 1,1-di- (n-butyl) -3- (2,3-dimethylphenyl) - white solid urea 15 CCCII 1,1-di- (n-butyl) -3- (2,5-dimethylphenyl) - „“ „urea CCCIII 1,1-di- (n-butyl) -3- (2,6-dimethylphenyl) - 131-134 urea CCCIV 1,1-di- (n-butyl) -3- (3,4-dimethylphenyl) - 74-76 20 urea CCCV 1 , 1-di- (n-butyl) -3- (3,5-dimethylphenyl) - white solid urea CCCVI 1,1-di- (n-butyl) -3- (2,4,6-trimethyl- 119 -120 phenyl) urea CCCVII 1,1-di- (n-butyl) -3- (4-methoxyphenyl) - white solid urea CCCVIII 1,1-di- (n-butyl) -3- (4-ethoxyphenyl ) - 59-60 urea CCCIX 1,1-di- (n-butyl) -3- (3-methyltiophenyl) - ^ 5-65 5 30 urea 'CCCX 1,1-di- (n-butyl) -3 - (2-chlorophenyl) - oil urea CCCXI 1,1-dl- (n-tatyl) -3- (3 -chaorophenyl) - „itta solid urea 35 CCCXIX 1,1-di- (n-butyl) -3- (4-fluorophenyl) -„ „„ urea CCCXIII 1,1-di- (n-butyl) -3 - (4-iodophenyl) - 113-114 urea t CCCXIV 1,1-di- (n-butyl) -3- (2 f 3-dichloro oil 40 phenyl) urea CCCXV 1,1-di- (n-butyl ) -3- (2,4-dichlorophenyl) - "urea 8300269 * v - -48- CCCXVI 1,1-di- (n-butyl) -3- (3,5-dichlorophenyl) - 80-81 urea CCCXVII 1 , 1-di- (n-butyl) -3- (2,3,5-trichloro solid phenyl) urea 5 CCCXVIII 1,1-di- (n-butyl) -3- (3-acetylphenyl) - 80-81 urea CCCXIX 1,1-di- (n-butyl) -3- (4-acetylphenyl) - 5 urea '' CCCXX 1,1-di- (n-butyl) -3- (3-chloro-2 73-75 methylphenyl) urea CCCXXI 1,1-di- (n-butyl) -3- (3-chloro-4-). _

methylphenyl) urea g V 6 S

CCCXXII 1,1-di- (n-butyl) -3- (3-chloro-4- 80-81 fluorophenyl) urea CCCXXIII 1,1-di- (n-butyl) -3- (2-chloro-4 - yellow solid mtrophenyl) urea CCCXXIV 1,1-di- (n-butyl) -3- (4-chloro-3- 84-85 trifluoromethylphenyl) urea CCCXXV 1,1-di- (sec- butyl) -3- (2,4-di-97-99 methylphenyl) urea CCCXXVI 1,1-di- (n-penty1) -3- (2,4-dimethyl-45-46 phenyl) urea CCCXXVII 1, 1-di- (n-isopentyl) -3- (2,4-dimethy1- - co -. - 00 - 00 phenyl) urea CCCXXVIII 1,1-di- (n-hexyl) -3- (2 , 4-dimethy1-oil phenyl) urea CCCXXIX 1,1-di- (n-heptyl) -3- (2,4-dimethy1- - - »*“ * QeXe oXXs phenyl) urea 'CCCXXX 1,1-di- (n-octyl) -3- (2,4-dimethyl-1, 30-phenyl) urea CCCXXXI 1,1-di- (n-undecyl) -3- (2,4-dimethyl-1-phenyl) ur etna g CCCXXXII 1,1-di- (n-decyl) -3- (2,4-dimethyl- „„ phenyl) urea 35 CCCXXXIII 1,1-di- (n-dodecyl-3- (2,4-dimethyl) - "" phenyl) urea CCCXXXIV 1,1-di- (n-nonyl) -3- (2,4-dimethyl- ..

phenyl) urea ° e CCCXXXV 1,1-di- (4-cyclohexyl) -n-butyl) -3- __ 40 (2,4-dimethylphenyl) urea CCCXXXVI 1,1-di- (cyclopentyl) -3- (2 , 4-dimethyl- __

-v 1jO ~ 1jO

phenyl) urea CCCXXXVII 1,1-di- (n-butyl) -3- (2,3-dibenzophenyl) urea solid solid 8300 26 9 --- - - - - a -49- CCCXXXVIII 1,1- di- (n-hutyl) -3- (4-chloro-2-meth.yl-white solid phenyl) urea CCCXXXIX 1,1-dicyclohexyl-3- (2,4-dimethyl- "" "phenyl) urea 5 CCCXL 1,1-di- (n-butyl) -3- (3-methoxyphenyl) - „„ „urea CCCXLI 1,1-di- (n-butyl) -3 - [(3,3-dibutyl) urea- "" "4-methylphenyl] urea CCCXLII 1,1-di- (isobutyl) -3- (2-chlorophenyl) -" "" 10 urea CCCXLIII 1,1-di- (isobutyl) -3- [3,3- diisobutyl) - tan-colored urea-4-methylphenyl] urea solid CCCXLIV 1,1-di- (isobutyl) -3- (2,5-dimethyl-Mitte solid 3t <phen phenyl) urea 15 CCCXLV 1,1-di - (isobutyl) -3- (2,6-dimethyl- „„ „phenyl) urea CCCXLVI 1,1-di- (n-butyl) -3- (5-chloro-2-methyl-55-56 'phenyl) urea CCCXLVII 1,1-di- (3,5,5-trimethylhexyl) - 69-70 20 3- (2,4-dimethylphenyl) urea

CCCXLVIII 1,1-di- (2-ethylhexyl) -3- (2,4-dimethyl-4Q

phenyl) urea

Example CCCXLIX

1,1-Di- (n-butyl) -3- (3-bromophenyl) urea * 25 A solution of 1.56 g of phenyl chloroformate in 50 ml of ether was added dropwise to a stirred solution of 3.44 g of 3-bromoaniline in 35 ml of ether and the mixture was stirred at room temperature for 1 hour and then filtered. The fltrate was evaporated, and the residue was crystallized from hexane to give phenyl N- (3-bromophenyl) carbamate, mp 88-90 ° C.

A solution of 1.46 g of phenyl N- (3-bromophenyl) carbamate in 15 ml of tetrahydrofuran was added to a solution of 1.52 g of di-n-butylamine in 20 ml of tetrahydrofuran, and the mixture was refluxed for 24 hours stirred for an hour. The mixture was diluted with hexane and the precipitate collected by filtration. Recrystallization from pentane gave 1,1-di- (n-butyl) -3- (3-bromophenyl) urea, m.p. 80-81 ° C.

8300269

Claims (3)

A compound of formula 1 of the formula sheet, wherein X represents at least one substituent selected from the group of hydrogen, alkyl of 1-4 carbon atoms, alkenyl of 1-4 carbon atoms, alkynyl of 1-4 carbon atoms, hydroxy, alkoxy of 1-4 carbon atoms, 5 phenoxy, mercapto, alkylthio with 1-4 carbon atoms, amino, alkylamino with 1-4 carbon atoms, dialkylamino in which each alkyl group has 1-4 carbon atoms, halogen, trihalomethyl, alkanoyl with 1-4 carbon atoms, benzoyl, alkanamido with 1-4 carbon atoms, alkanesulfonyl with 1-4 'carbon atoms, alkanesulfinyl with 1-4 carbon atoms, benzenesulfonyl, toluene sulfonyl, nitro, cyano, carboxy, carboalkoxy with 1-4 carbon atoms, carbamoyl, sulfamyl, methylenedioxy, phenyl, ortho -phenylene, tolyl, benzyl, halobenzyl, methylbenzyl, and the group of formula 2; wherein Y is selected from the group of oxygen and sulfur; R 1 and are the same or different and are independently selected from the group of alkyl of 4-12 carbon atoms, alkenyl of 4-12 carbon atoms, alkynyl of 4-12 carbon atoms, cycloalkyl of 4-12 carbon atoms, cycloalkylalkyl of 4-12 carbon atoms, aralkyl of 7-14 carbon atoms, and aralkyl of 7-14 carbon atoms in which an aromatic ring carries at least one substituent selected from the group of alkyl of 1-10 carbon atoms, alkoxy of 1-10 carbon atoms, phenoxy, benzyloxy, methylenedioxy alkylthio of 1-4 carbon atoms, phenyl, halogen, trihalomethyl, adamantyl, carboalkoxy of 1-4 carbon atoms, and nitro; and is selected from the group consisting of hydrogen, alkyl of 1-4 carbon atoms, alkenyl of 1-4 carbon atoms, alkynyl of 1-4 carbon atoms, benzyl, benzyl with at least one substituent Z, naphthyl, phenyl, and phenyl with at least one substituent Z, wherein Z is independently selected from X from the group from which X is selected, and R ^ and R ^ are not hydrogen when R ^ is hydrogen. A compound according to claim 1, wherein Y is oxygen. The compound of claim 1, wherein X represents at least one halo substituent. The compound of claim 1, wherein X represents at least one substituent selected from the group of alkyl of 1-4 carbon atoms, alkoxy of 1-4 carbon atoms, halogen, carboalkoxy of 1-4 carbon atoms, and benzyl. 83 0 0 2 6 9 · ------------------------------------- ------ I _ _ * -51- A process for preparing compounds of formula la, wherein a compound of formula 5 wherein Y is as defined in claim 7 and A and B are independently selected from the group of halogen, alkoxy of 1-4 carbon atoms, alkylthio of 5 1-4 carbon atoms, phenoxy, 4-chlorophenoxy, and 4-nitrophenoxy; react with an arylamine of formula 7 wherein X has the meanings set forth in claim 7 to form an intermediate of formula 8, and then the intermediate is reacted with a secondary amine of formula 4 wherein R 1 and R 2 are in claim Have 7 meanings listed. A method of preparing compounds as defined in claim 5, wherein a compound of formula 5 wherein Y is as defined in claim 5 and A and B are independently selected from the group of halogen, alkoxy of 1-4 carbon atoms alkylthio 15 with 1-4 carbon atoms, phenoxy, 4-chlorophenoxy, and 4-nitrophenoxy; react with a secondary amine of formula 4 wherein R 1 and R 2 are as defined in claim 5, whereby an intermediate of formula 6 is obtained, and the intermediate is reacted with an arylamine of formula 7 wherein X is as defined in claim 5 Has 20 meanings. A process for preparing compounds of formula la of the formula sheet, wherein X represents at least one substituent selected from the group of hydrogen, alkyl of 1-4 carbon atoms, alkenyl of 1-4 carbon atoms, alkynyl of 1-4 carbon atoms, hydroxy, alkoxy of 1-4 carbon atoms, phenoxy, mercapto, alkylthio of 1-4 carbon atoms, amino, alkylamino of 1-4 carbon atoms, dialkyl amino in which each alkyl group has 1-4 carbon atoms, halogen, tri-halomethyl, alkanoyl of 1-4 carbon atoms, benzoyl, alkane amido of 1-4 carbon atoms, alkanesulfonyl of 1-4 carbon atoms, alkane-30 sulfinyl of 1-4 carbon atoms, benzenesulfonyl, toluenesulfonyl, nitro, cyano, carboxy, carboalkoxy of 1-4 carbon atoms, carbamoyl, sulfamyl, methylenedioxy, phenyl, ortho-phenylene tolyl, benzyl, halobenzyl, methylbenzyl, and the group of formula 2; Y is selected from the group of oxygen and sulfur; R 1 and R 2 are the same or different and are independently selected from the group of alkyl of 4-12 carbon atoms, alkenyl of 4-12 carbon atoms, alkynyl of 4-12 83 0 0 2 6 9 ...... ..... · ...... ~ 7 l 'ί. .................. .................................................. . __ ______________________________________________________ ________________ -52- carbon, cycloalkyl of 4-12 carbon atoms, cycloalkylalkyl of 4-12 carbon atoms, aralkyl of 7-14 carbon atoms, and aralkyl of 7-14 carbon atoms in which an aromatic ring bears at least one substituent selected from the group alkyl of 1-10 carbon atoms, alkoxy of 1-10 carbon atoms, phenoxy, benzyloxy, methylenedioxy, alkylthio of 1-4 carbon atoms, phenyl, halogen, trihalomethyl, adamantyl, carboalkoxy of 1-4 carbon atoms, and nitro; wherein an aryl isocyanate or arylthiol'socyanate of formula 3 is reacted with a secondary amine of formula 4 wherein symbols X, Y, and Rj are defined as above. 8. A method of treating atherosclerosis, lowering the cholesterol ester content of the arterial wall, inhibiting the development of atherosclerotic lesions and / or treating hyperlipidemia in a mammal in need of such treatment, including the mammal administering an effective amount of a compound of formula 1, wherein X represents at least one substituent selected from the group of hydrogen, alkyl of 1-4 carbon atoms, alkenyl of 1-4 carbon atoms, alkynyl of 1-4 carbon atoms, hydroxy, alkoxy of 1-4 carbon atoms, phenoxy, mercapto, alkylthio of 1-4 carbon atoms, amino, alkylamino of 1-4 carbon atoms, dialkylamino in which each alkyl group has 1-4 carbon atoms, halogen, trihalomethyl, alkanoyl with 1-4 carbon atoms, benzoyl, alkane amido with 1-4 carbon atoms, alkanesulfonyl with 1-4 carbon atoms, alkanesulfinyl with 1-4 carbon atoms, benzenesulfonyl, toluenesulfonyl, nitro, cyano, carboxy, carboalkoxy of 1-4 carbon atoms, carbamoyl, sulfamyl, methylenedioxy, phenyl, ortho-phenylene tolyl, benzyl, halobenzyl, methylbenzyl, and the group of formula 2, Y is selected from the group of oxygen and sulfur; and Rj are the same or different and are independently selected from the group of alkyl of 4-12 carbon atoms, alkenyl of 4-12 carbon atoms, alkynyl of 4-12 carbon atoms, cycloalkyl of 4-12 carbon atoms, cycloalkylalkyl of 4-12 carbon atoms, aralkyl of 7-14 carbon atoms, and aralkyl of 7-14 carbon atoms in which an aromatic ring carries at least one substituent selected from the group of alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, phenoxy, benzyl oxy, methylenedioxy, alkylthio with 1-4 carbon atoms, phenyl, halo 8 3 0 0 2 6 9 ............. * s -53- none, trihalomethyl, adamantyl, carboalkoxy with 1- 4 carbon atoms / and nitro; and R 4 is selected from the group consisting of hydrogen, alkyl of 1 to 4 carbon atoms, alkenyl of 1 to 4 carbon atoms, alkynyl of 1 to 4 carbon atoms, benzyl, benzyl with at least one substituent Z, 5 naphthyl, phenyl, and phenyl with at least at least one substituent Z, wherein Z is independently selected from X from the group from which X is selected. A pharmaceutical composition, suitable for treating atherosclerosis, lowering the cholesterol ester of the arterial wall, inhibiting the development of atherosclerotic lesions and / or treating hyperlipidemia in a mammal in need of such treatment, comprising an active amount of a compound of formula 1, wherein X represents at least one substituent selected from the group of hydrogen, alkyl of 1-4 carbon atoms, alkenyl of 1-4 carbon atoms, alkynyl of 1-4 carbon atoms, hydroxy, alkoxy of 1- 4 carbon atoms, phenoxy, mercapto, alkylthio with 1-4 carbon atoms, amino, alkylamino with 1-4 carbon atoms, dialkylamino in which each alkyl group has 1-4 carbon atoms, halogen, trihalomethyl, alkanoyl with 1-4 carbon atoms, benzoyl, alkane atnido with 1- 4 carbon atoms, alkanesulfonyl with 1-4 20 carbon atoms, alkanesulfinyl with 1-4 carbon atoms, benzenesulfonyl, toluenesulfonyl, nitro, cyano, ca r boxy, carboalkoxy of 1-4 carbon atoms, carbamoyl, sulfamyl, methylenedioxy, phenyl, ortho-phenylene tolyl * benzyl, halobenzyl, methylbenzyl, and the group of formula 2; Y is selected from the group of oxygen and sulfur? R ^ and R ^ are the same or different and are independently selected from the group of alkyl of 4-12 carbon atoms, alkenyl of 4-12 carbon atoms, alkynyl of 4-12 carbon atoms, cycloalkyl of 4 -12 carbon atoms, cycloalkylalkyl of 4-12 carbon atoms, aralkyl of 7-14 carbon atoms, and aralkyl of 7-14 carbon atoms in which an aromatic ring carries at least one substituent selected from the group of alkyl with 1-10 carbon atoms, alkoxy with 1-10 carbon atoms, phenoxy, benzyloxy, methylenedioxy, alkylthio with 1-4 carbon atoms, phenyl, halogen, trihalomethyl, adamantyl, carboalkoxy with 1-4 carbon atoms, and nitro? and is selected from the group of hydrogen, alkyl of 1-4 carbon atoms, alkenyl of 1-4 carbon atoms, alkynyl of 1-4 carbon atoms, benzyl, benzyl with at least one substituent Z, naphthyl, phenyl, and phenyl with at least at least one substituent Z, wherein Z is independently selected from X from the group from which X is selected. ................ 8300269 MS R3 Y R1 1ü HY Rx \ u / η \ υ ^ HêT "'. N / 2 2α Ri υ Ηχ Y \" / Vc-X NCN X \ o '\ R2 r3 3 k 5 3 RX ^ / = C = Y K «X — fö) \ 2 A-c-B 6 7 I / Rl _ NH" -Htr 8 Hx I "HtT" American Cyanamid Company 8300269