DK160869B - ANALOGY PROCEDURE FOR THE PREPARATION OF SUBSTITUTED URINES AND THIOUR INGREDIENTS - Google Patents

Description

in

DK 160869 B

The present invention relates to an analogous process for the preparation of novel substituted urea and thiourea compounds which can be used as pharmaceutical agents. The compounds of the invention are antiatherosclerotic agents capable of ameliorating atherosclerosis by counteracting the formation or development of atheromatous lesions in mammalian artery walls. Pharmaceutical compositions containing the compounds of the invention can be used to treat mammalian diseases, i.e. for preventing, stopping or improving the course of the disease.

DE Publication No. 29 28 485 describes urea compounds which are useful in the treatment of atherosclerosis and hyperlipidemia.

Atherosclerosis is a form of arteriosclerosis characterized by lipid accumulation and thickening of the arterial walls in both medium and large arteries. The arterial walls are thereby weakened and the elasticity and effective internal size of the artery are diminished. Atherosclerosis is the most common cause of ischemic heart disease and is of great medical importance as occlusion of the medium and large arteries reduces blood supply to vital organs such as heart muscle and the brain. The sequelae of atherosclerosis include ischemic heart disease, heart failure, life-threatening p arrhythmias, senility and stroke.

The fact that cholesterol is a predominant component of atherosclerotic lesions or plaques has been known for more than 100 years. Various researchers have investigated the role of cholesterol in the formation of lesions and the development thereof and likewise, which is of greater importance whether lesion formation can be prevented or the development of lesions can be stopped or cured. Atheromatous lesions have now been found (Adams et al., Atheroscleorsis, 13, 429 (1974)) to contain a greater amount of esterified - as opposed to non-esterified - cholesterol than the surrounding healthy artery wall. The

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2 intracellular esterification of cholesterol with fatty acids is catalyzed by the enzyme fatty acyl CoA: cholesterol acyltransferase or ACAT, and the accumulation and storage of cholesterol esters in the arterial wall is linked to an increased activity of this enzyme [Hashimoto and Dayto, Atherosclerosis, 28, 447 )]. In addition, cholesterol esters are removed more slowly from cells than unesterified cholesterol [Bondjers and Bjorkerud, Atherosclerosis, 15, 273 (1972) and 22, 379 (1975)]. Thus, inhibition of the ACAT enzyme would decrease cholesterol esterification rate, decrease 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 invention are very potent inhibitors of the ACAT enzyme and in this respect exhibit a superior effect over the compounds known from the aforementioned DE Publication No. 2,928,485. Thus, the compounds of the invention are useful for regulating and reducing the content of cholesterol ester in mammalian artery walls and for reducing the accumulation and storage of cholesterol in mammalian artery walls. In addition, the compounds inhibit the formation or development of mammalian artherosclerotic lesions.

The statement that hyperlipidemia is one of the factors involved in coronary heart disease is of great importance. An extremely important study, conducted in Framingham, Massachusetts (Gordon and Verter, 1969) of more than 5000 people for more than 12 years, establishes a link between high blood cholesterol levels and increased risk of heart attack.

30 Although the causes of coronary artery disorders are many, one of the most constant factors is elevated lipid concentration in the blood plasma. A combined increase of cholestrol and triglycerides has been found (Carlson and Bottiger, 1972) to carry the greatest risk of coronary heart disease. The majority of 35

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3 patients with ischemic heart disease or peripheral vascular disease were found to have hyperlipoproteinemia involving very low and / or low density lipoproteins (Lewis et al., 1974).

It has now been found that certain compounds of this type are capable of safely and effectively lowering both serum lipids in warm-blooded animals. Such an effect on serum lipids is considered to be very useful in the treatment of α-therosclerosis. For some time, it has been considered desirable to lower serum lipid levels and adjust mammalian lipoprotein imbalance as a preventive measure against atherosclerosis. The compounds of the invention do not act to block late steps in cholesterol biosynthesis and thus do not cause any accumulation of intermediates such as desmosterol which is as undesirable as cholesterol itself. Compounds having the combination of therapeutically beneficial characteristics of the compounds of the invention can be administered without risk to warm-blooded mammals for the treatment of hyperlipidaemic and atherosclerotic conditions occurring in patients with or prone to heart attacks, for disorders of the peripheral vessels or in the brain vessels and for stroke.

The compounds of the invention have antiatherosclerotic activity, but the invention is not bound to any particular mechanism of anti-atherosclerotic activity.

The invention relates to an analogous process for the preparation of novel substituted urea or thiourea compounds of the general formula I

\ II / I

N-C-N

X-4øT Sr2 35

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4 wherein X is at least one substituent selected from hydrogen,

C 1-4 alkyl, hydroxy, C 1-4 alkoxy, phenoxy, amino, halogen, trihalomethyl, C 1-4 alkylamido and nitro, Y is oxygen or sulfur, R 5 and R 2 are different and are each selected from C 4-12 alkyl, C4-12 cycloalkylalkyl, C7_14-phenylalkyl and C7_14-phenylalkyl, wherein the phenyl ring carries at least one substituent selected from C1-10 alkyl, C1-6 alkoxy, phenoxy, benzyloxy, methylenedioxy, C1-4 alkylthio, phenyl, halo, trihalomethyl, R 3 is selected from hydrogen, C 1-4 alkyl, benzyl, benzyl with at least one substituent Z, naphthyl, phenyl and phenyl with at least one substituent Z, wherein Z is selected independently of X from the meanings given for X, which process is characterized by the characterizing part of claim 1.

Preferred compounds prepared by the process of the invention are those wherein Y is oxygen. Further preferred are those wherein X is at least one C 1-4 alkyl or halogen substituent and R 11 and R 2 are selected from α 1-12 alkyl, C 7-14 phenylalkyl and substituted C 7-14 phenylalkyl. The most preferred are those wherein X is at least one methyl or chlorine substituent and Z is hydrogen, methyl or chlorine.

Particularly preferred compounds of the invention are 1- (n-heptyl) -1- [4- (2,2-dimethylpropyl) phenylmethyl] -3- (2,4-difluorophenyl) urea, 1- (n heptyl) -1- [4- (2,2-dimethylpropyl) phenylmethyl] -3- (4-chloro-2,6-dimethylphenyl) urea and 1- (n-heptyl) -1- [4- (2,2-dimethylpropyl) phenylmethyl] 1-3- (2,4,6-trifluorophenyl) urea.

In process variant c), an arylisocyanate or an arylthioisocyanate of the formula is reacted

^ V = C = Y HI

35 X_T @

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5 with a secondary amine of the formula

Hi / 1

"R2 IV

5 where X, Y, Rx and R2 have the meanings set forth above.

In process variant b), a compound of the formula is reacted

Y

10 "

A-C-B V

wherein Y is as defined above, and A and B are each selected from halogen, C 1-4 alkoxy, C 1-4 alkylthio, phenoxy, 4-chlorophenoxy and 4-nitrophenoxy, with a secondary amine of formula IV to give an intermediate of the formula? Λ

A-C-N ^ X VI

And the intermediate is reacted with an aryl amine of the formula

Raw

am

X - (0} VII

wherein X and R3 have the meaning given above.

In process variant a), a compound of formula V is reacted with an aryl amine of formula VII to give an intermediate of formula

R3 Y

\ Il

/ sJ-C-B VIII

And then the intermediate is reacted with a secondary amine of formula IV.

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6

For the treatment of atherosclerosis, lowering the cholesterol-cholesterol content of the arterial wall, inhibiting the development of artherosclerotic lesion and / or for the treatment of hyperlipidemia in mammals in need of such treatment, an effective amount of a compound of formula I is administered to the mammal.

A pharmaceutical composition suitable for treating atherosclerosis, lowering the cholesterol ester content of the arterial wall, inhibiting development of atherosclerotic lesion, and / or treating hyperlipidemia in a mammal in need of such treatment can be prepared by providing an effective amount of a compound with the formula I is combined with a non-toxic pharmaceutically acceptable carrier.

Certain of the present ureas and thioureas are prepared by reacting activated derivatives of carboxylic acid such as phosgene, thiophosgene or phenyl chloroformate with secondary amines to give an intermediate, e.g. a di-substituted carbamyl chloride. This intermediate is then reacted with an aryl amine to give the urea or thiourea. The intermediate product is prepared in an aprotic solvent such as tetrahydrofuran, toluene, xylene or the like at temperatures of about room temperature up to the boiling point of the solvent. The intermediate can be isolated by evaporation and purified by distillation if necessary. The intermediate is then reacted with an aryl amine in an aprotic solvent such as dimethylacetamide in the presence of a base such as sodium hydride at temperatures ranging from ca. room temperature up to the boiling point of the solvent. An example of this process is the reaction of phosgene with N-benzyl-n-butylamine in toluene to give the intermediate N-benzyl-N- (n-butyl) carbamyl chloride, which is then reacted with diphenylamine in Ν, Ν-dimethylacetamide in the presence of sodium hydride to give 1-benzyl-1- (n-butyl) -3,3-diphenyl urea.

Other ureas and thiourine substances of this invention are prepared by reacting arylamines with activated dehydrogenase.

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7 levels of carboxylic acid such as phosgene or thiophosgene giving an intermediate, e.g. an aryl carbamyl chloride. This intermediate is then reacted with a secondary amine to give the urea or thiourea. The preparation of this intermediate takes place in an aprotic solvent such as tetrahydrofuran, toluene or xylene at temperatures ranging from approx. room temperature up to the boiling point of the solvent in the presence of a base, e.g. Ν, Ν-dimethylaniline. The intermediate is then reacted with a secondary amine in an aprotic solvent such as a toluene at room temperature or below up to the boiling point of the solvent. An example of this process is the reaction of phosgene with N-phenyl-3-chloroaniline to give the intermediate N- (3-chlorophenyl) -N-phenyl-carbamyl chloride, which is then reacted with N-rbenzyl-n-butylamine to give 1-benzyl-1- (n-butyl) -3- (3-chlorophenyl) -3-15-phenylurea.

The ureas and thioureas of formula I containing carboxy groups are prepared by alkaline hydrolysis of the corresponding carboxyoxyureas and thioureas, prepared by the method described above. Similarly, those containing hydroxy, mercapto or amino groups are prepared. by alkaline hydrolysis of the corresponding O-acetyl, S-acetyl and N-acetylureas and thioureas, the latter also being obtained by the urea and thiourea syntheses described above. Alternatively, ureas and thioureas containing hydroxy groups are prepared by cleavage of the corresponding methoxy compound by Lewis acids such as boron tribromide.

Certain substituted N-benzylanilines, which are intermediates necessary for the synthesis of some of the 30 tetrasubstituted ureas and thioureas of formula I, are novel. The necessary N-benzylanilines are prepared by reacting different benzaldehydes with anilines to give aniles. The aniles are then reduced to give the substituted N-benzylanilines. An example of such a synthesis involves reacting 2,4-dimethylbenz aldehyde with 2,4-dichloroaniline to give N- (2,4-dimethylbenzylidene) -2,4-dimethylbenzylidene) -2,4-dichloroaniline .

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. 8 followed by reduction with sodium borohydride to give N- (2,4-dimethylbenzyl) -2,4-dichloroaniline.

Many of the ureas and thioureas of formula I are prepared by reacting arylisocyanates and arylisothiothiocyanates with secondary amines. These reactions can be carried out in aprotic solvents such as hexane, diethyl ether, toluene, tetrahydrofuran and the like at temperatures from room temperature or below up to the boiling point of the solvent used. The ureas and thioureas are isolated by filtration or by evaporation of the solvent and they can be purified by recrystallization, absorption chromatography or distillation under reduced pressure. An example of this process is the reaction of 2,4-dimethylphenylisocyanate with di- (n-butyl ) amine to give 1,1-di- (n-butyl) -3- (2,4-dimethylphenyl) urea.

Many of the secondary amines to be used for the synthesis of the urea and thioureas of formula I are obtained by diborane reductions of the corresponding amides. An example of this reaction is the synthesis of N- (n-20-butyl) -2-chlorobenzylamine by diborane reduction of N- (n-butyl) -2-chlorobenzamide. Certain of the amides needed for these reductions are prepared by acylating primary amines with carboxylic acids by methods well known in the art, e.g. by converting the carboxylic acid to the corresponding carboxylic acid chloride using thionyl chloride, and then reacting the acid chloride with the primary amine in the presence of a base. One method particularly useful for this conversion is a catalyst reaction with boron trifluoride etherate between carboxylic acid and a primary amine. An example of this conversion is boron trifluoride etherate catalyzed acylation of 2-chlorobenzylamine with 3-methoxyphenylacetic acid to give N- (2-chlorobenzyl) -3-methoxyphenylacetamide.

The ureas and thioureas of formula I are available as 35 crystalline solids or distillable liquids. They are characterized by distinct melting or boiling points and uni-

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9 0 ke spetre. They are clearly soluble in organic solvents, but generally more soluble in water. The compounds containing carboxylic acid groups can be converted to their alkali metal and alkaline earth metal salts by treatment with suitable metal hydroxides and those containing amino groups can be converted to ammonium salts by treatment with organic or mineral acids. Both of these types of salts exhibit increased solubility in water.

The properties and scope of the compounds of the invention will be elucidated in the specific tables below.

The compounds of the invention are tested for two types of biological activity associated with their possible use as antiatherosclerotic agents. The compounds are tested in vitro for their ability to inhibit the fatty acyl CoArcholesterolacyltransferase (ACAT) enzyme and in vitro for serum hypolipidemic activity as measured by their ability to inhibit lipid absorption in rats. The compounds are tested for their ability to inhibit ACAT by the following method:

Rat adrenals are homogenized in Q, 2 molar monobasic potassium phosphate buffer, pH 7.4, and centrifuged at 1Q00G for 15 minutes at 5 ° C. The supernatant layer containing the microsomal fraction acts as a source of the cholesterol esterification enzyme, fatty acyl CoA: cholesterol-acyl transferase (ACAT). A mixture of 50 parts of the liquid on top; layers, 10 parts albumin (BSA) (50 mg / ml), 3 parts test compound (final concentration 5.2 g / ml) and 500 parts buffer are preincubated at 37 ° C for 10 minutes. After treatment with 20 parts of 14 oleoyl CoA (C-0.4 Ci), the mixture is incubated at 37 C for 10 minutes. A control mixture in which per the compound is omitted is prepared and treated in the same way. The lipids from the incubation mixture are extracted into an organic solvent and separated by thin layer chromatography. The cholesterol ester fraction is counted in a scintillation counter. This method is a modification of that described by Hashimoto et al. in Life Science, 12 (Part II), 1-12 (1973).

The results of this test on representative compounds

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10 results obtained by the method of the invention are shown in Table I.

Table I 5

Compound% inhibition of 1-Benzyl-1- (n-butyl) -3,3-diphenylurea 75.9 1-Benzyl-1- (n-butyl) -3- (3-chlorophenyl) -3-phenylurea 72, 3 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- (3-methylphenyl) -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 1-Benzyl-1- (n-butyl) -3- (1-naphthyl) -3-phenyl-urea 76,3 1-Benzyl-1- (n-butyl) -3- (2-naphthyl) -3- (3-chlorophenyl) urea 82,7 1-Benzyl-urea 1- (n-butyl) -3- (3-methylphenyl) urea 92.3 1-Benzyl-1- (n-butyl) -3- (3-trifluoromethylphenyl) urea 85.7 1-Benzyl-1- (n-butyl) -3- (3,5-dichlorophenyl) urea 90.7 1-Benzyl-1- (n-butyl) -3- (3,4-dichlorophenyl) urea 95.9 1-Benzyl-1- (n-butyl) -3- (3-chlorophenyl) urea 88.6 1-Benzyl-1- (n-butyl) -3- (2,4-dimethylphenyl) urea 91.3 1-Benzyl-1- ( n-butyl) -3- (2-methylphenyl) urea 78.8 1-Benzyl-1- (n-butyl) -3- (4-methyl) thylphenyl) urea 78.0 1-Benzyl-1- (n-butyl) -3- (2,3-dimethylphenyl) urea 85.8 1-Benzyl-1- (n-butyl) -3- (2,5- dimethylphenyl) urea 92.7 1-Benzyl-1- (n-butyl) -3- (2,6-dimethylphenyl) urea 83.1 1-Benzyl-1- (n-butyl) -3- (3.5 (dimethylphenyl) urea 94.2

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° Table I (continued)

Compound% Inhibition 1-Benzyl-1- (n-butyl) -3- (3,4-dimethylphenyl) urea 87.1 1-Benzyl-1- (n-butyl) -3- (3-chloro-2-methoxyphenyl) ) urea 84.5 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-Butyl) -1- (4-fluorobenzyl) -3- (2,4-dimethylphenyl) urea 80.6 1- (n-Butyl) -1- (2-chlorobenzyl) -3- (2,4-dimethylphenyl) urea 95.5 1- (n -Butyl) -1- (2,6-dichlorobenzyl) -3- (2,4-dimethylphenyl) urea 74.5 1- (n-Butyl) -1- (4-bromobenzyl) -3- (2, 4-dimethylphenyl) urea 81.0 1- (n-Butyl) -1- [4- (n-butyl) benzyl)] - 3- (2,4-dimethylphenyl) urea 94.4 1- ( n-Butyl) -1- (4-methylbenzyl) -3- (2,4-dimethylphenyl) urea 96.7 1- (n-Butyl) -1- (4-tert.butylbenzyl) -3- (2.4 -dimethyl-phenyl) urea 96.4 1- (n-Butyl) -1- (4-chlorobenzyl) -3- (2,4-dimethylphenyl) urea 94.6 1- (n-Butyl) -1- ( 4-methoxybenzyl) -3- (2,4-dimethylphenyl) urea 94.2 1- (n-Butyl) -1- (3,4-methylenedioxybenzene) zyl) -3- (2,4-dimethylphenyl) urea 88.2 1- (n-Butyl) -1- (4-trifluoromethylbenzyl) -3- (2,4-dimethylphenyl) urea 93.3 - (n-Butyl) -1- (4-phenylbenzyl) -3- (2,4-dimethyl-phenyl) urea 97.1 1- (n-Decyl) -1-benzyl-d- (2,4- dimethylphenyl) - urea 96.1 o Table I (continued)

Compound __% inhibition 12

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1- (n-Butyl) -1- (2-phenylethyl) -3- (2/4-dimethylphenyl) urea 87.9 1- (n-Butyl) -1- [2- (4-fluorophenyl) ethyl] -3- (2,4-dimethylphenyl) urea 96.1 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 1- (n-Butyl) -1-benzyl-3- (2,4,6-trimethylphenyl) - urea 75.8 1- ( n-Butyl) -1- [4- (n-hexyl) benzyl] -3- (2,4-dimethylphenyl) urea 93.8 1- (n-Tetradecyl) -1-benzyl-3- (2 4,3-dimethylphenyl) urea 80,3 1- (n-Octadecyl) -1-benzyl-3- (2,4-dimethylphenyl) -2Q urea 80,3 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- [2- (3,4-Dimethoxyphenyl) ethyl] -1- (3-chloro-4-methylbenzyl) -r3- (2,4-dimethylphenyl) urea 53.3 1- [2- (2- Methylphenyl) ethyl] -1- (4-bromobenzyl) -3- (2,4-dimethylphenyl) urea 29.2 1- [2- (3-trifluoromethylphenyl) et hyl] -1- (2-chlorobenzyl) -3- (2,4-dimethylphenyl) urea 7.8 1- (2-Fluorobenzyl) -1- (2-methoxybenzyl) -3- (2,4-dimethylphenyl) urea dimethylphenyl) urea 41.5 1- [2- (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

ISLAND

Table I (continued)

Compound% inhibition 13

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1- [2- (3-Methylphenyl) ethyl] -1- (3-nitrobenzyl) -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-2,2-diphenyl) ethyl-3 - ( 2,4-dimethylphenyl) urea 97.4 1- (n-Butyl) -1- (4-hexylloxybenzyl) -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-trifluoroacetylamino, 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-trimethyl-phenyl) urea 92,8 1-Benzyl-1- (4-n-butylbenzyl) -3- (4-n-butylphenyl) urea 92.0 1-Benzyl -1- (4-n-butylbenzyl) -3- (4-phenoxyphenyl) urea 93.5 1- (n-Heptyl) -1- (4-n-butylbenzyl) -3- (2,4-dimethylphenyl) urea 94.8 1- (n-Heptyl) -1- (4-n-butylbenzyl) -3- (2,4,5-trimethylphenyl) urea 95.3 1- (n-Heptyl) -1- (4-butyloxybenzyl) -3- (2,4-dimethyl-phenyl) urea 94.6 1- (n-Heptyl) -1 (4-butyloxy) benzyl) -3- (2,4,5-trimethylphenyl) urea 95,6 1-Benzyl-1- (4-butyloxybenzyl) -3- (2,4-dimethylphenyl) urea 91.7-1 Benzyl-1- (4-butyloxybenzyl) -3- (2,4,5-trimethylphenyl) urea 95.8 1- (9-Octadecenyl) -1- (4-n-butylbenzyl) -3- (2, 4-dimethylphenyl) urea 42.2 35

ISLAND

14

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Compound% Inhibition 1-Benzyl-1- (4-n-butylbenzyl) -3- (2,4,5-trimethyl-phenyl) urea 90.5 1- (9-Octadecenyl) -1- (4-n-butylbenzyl) ) -3- (2,4,5-5-trimethylphenyl) urea 9,4 1- (n-Heptyl) -1- (4-n-butoxybenzyl) -3- (2,4,6-trichlorophenyl) urea 90.0 1- (n-Heptyl) - (4-n-butoxybenzyl) -3- (2,4-dichloro-phenyl) 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-trichloro-phenyl) urea 95.2 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-trifluoromethylphenyl) urea 82.4 1- (n-Benzy1-1 - (4-n-butoxybenzyl) -3- (3-trifluoromethylphenyl) urea 87.0 1- (n-Heptyl) -1- (4-n-butylbenzyl) -3- (2,4-dichloro-phenyl) ) urea 80.0 1- (n-Heptyl) -1- (4-n-butylbenzyl) -3- (2-trifluoromethyl-4-chlorophenyl) urea 90.0 1- (n-Heptyl) -1 - (4-n-butylbenzyl) -3- (2,4,6-trichloro-phenyl) urea 90.0 1- (n -Heptyl) -1- (4-n-butylbenzyl) -3- (3-trifluoromethyl-phenyl) urea 85.0 1- (n-Heptyl) -1- (4-n-butylbenzyl) -3- (2 4,5-Trichlorophenyl) urea 46.5 1-Benzyl-1- (4-n-butylbenzyl) -3- (2-methyl-4-chloro-phenyl) 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 -methyl-4-chlorophenyl) urea 91.7 Table I (continued)

Compound% inhibition 15

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1- (n-Heptyl) -1- (4-n-butylbenzyl) -3- (2-methyl-4-chlorophenyl) urea 92.5 1 "(n-Heptyl) -1- (4-n- butylbenzyl) -3- (2,4-difluorophenyl) urea 90.0 1- (n-Heptyl) -1- (4-n-butylbenzyl) -3- (2-methylphenyl) urea 97.4 1 - (n-Heptyl) -1- (4-n-butylbenzyl) -3- (3-methylphenyl) urea 93.8 1- (n-Heptyl) -1- (2-phenylethyl) -3- ( 2-methyl-4-chlorophenyl) urea 93.8 1- (n-Heptyl) -1- (2-phenylethyl) -3- (2,4,5-trichloro-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-Dimethyl-phenyl) urea 95.7 1- (n-Heptyl) -1- (2-phenylethyl) -3- (2,4-dichlorophenyl) urea 91.8 1- (n-Heptyl) - 1- (2-phenylethyl) -3- (2,4-difluorophenyl) urea 94.1 1- (n-Heptyl) -1- (2-phenylethyl) -3- (3-trifluoromethylphenyl) urea 88 1- (4-n-Pentylbenzyl) -1- (4-n-pentyloxybenzyl) -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) -3 -30 - (2,4,5-trichlorophenyl) urea 80.0 1- (4-n-Pentylbenzyl) -1- (4-n-pentyloxybenzyl) -3- (2-trifluoromethyl-4-chlorophenyl) urea 81 1- (4-n-Pentylbenzyl) -1- (4-n-pentyloxybenzyl) -3- (3-trifluoromethylphenyl) urea 85 0 35

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16 q Table I (continued)

Compound% inhibition 1- (4-n-Pentylbenzyl) -1- (4-n-pentyloxybenzyl) -3- (2,4-difluorophenyl) urea 90.0 1- (4-n-Pentylbenzyl) -1- ( 4-n-pentyloxybenzyl) -3- (2-methyl-4-chlorophenyl) urea 91.0 1- (4-Chlorobenzyl) -1- (1-naphthylmethyl) -3- (2,4,6-) Trichlorophenyl) urea 77.0 1- (4-Chlorobenzyl) -1- (1-naphthylmethyl) -3- (2-methyl-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 1 - (4-Chlorobenzyl) -1- (1-naphthylmethyl) -3- (2,4,5-15-trichlorophenyl) urea 86.0 1-Benzyl-1- (4-n-butyloxybenzyl) -3- (2 4,5-Trichloro-phenyl) urea 89.0 1-Benzyl-1- (4-n-butoxybenzyl) -3- (2,4-difluorophenyl) urea 88.0 1- (4-Chlorobenzyl) -1 - (1-Naphthylmethyl) -3- (2,4-dichlorophenyl) urea 92.0 1- (4-Chlorobenzyl) -1- (1-naphthylmethyl) -3- (2-trifluoromethyl-4-chlorophenyl) urea 83.0 3- (2,4-difluorophenyl) -1 - [[4- (2,2-dimethylpropyl) phenyl] methyl] -1-heptyl urea 95 3- (4-chloro) r-2,6-dimethylphenyl) -1 - [[4- (2,2-dimethylpropyl) phenyl] -1-heptyl urea 95 1 - [[4- (2,2-dimethylpropyl) phenyl] methyl] - 1-30 -heptyl-3- (2,3,6-trifluorophenyl) urea 95 17

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Inhibition of cholesterol absorption is determined by feeding a male Sprague-Dawley weighing 150-170 g with 1% cholesterol: 0.5% cholic acid for 2 weeks. The feed also contains tested compounds at a dose of 0.03% 5 of the feed. Control rats receive the same feed without compound.

At the end of the test, the rats are killed by having their heads chopped off. The blood is collected, centrifuged at 1.5 G for 10 minutes at 4 ° C and then enzymatically analyzed for serum cholesterol and triglycerides by P.Trinder's method, 10 Analyst, 77, 321 (1952) on a "Centrifichem 400 Analyzer" .

The livers are removed, a sample of 0.4 g is taken from the center of the large patch, and the sample is hydrolyzed using 25% saturated potassium hydroxide in ethanol. The resulting neutral sterols are extracted with petroleum ether and the extract is analyzed for cholesterol sterol. The efficacy of the compound to inhibit cholesterol absorption is measured by its ability to lower either serum cholesterol or liver cholesterol compared with the values obtained in control rats. .

Compounds which provide a statistically significant inhibition of cholesterol absorption are considered active. Liver - sterol (LS) and serum sterol (SS) values are expressed as a percentage of the control value. The results of this study are shown in Table 1a.

Table 1a

Forbindelse__LS_SS

3- (2,4-difluorophenyl) -1 - [[4- (2,2-dimethyl-propyl) phenyl] methyl] -1-heptyl-urea 3- (4-chloro-2,6-dimethylphenyl) -1 - [[4- (2,2-30-dimethylpropyl) phenyl] -1-heptyl urea 17 1 - [[4- (2,2-dimethylpropyl) phenyl] methyl] -1-heptyl-3 - (2,4,6-trifluorophenyl) urea

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When the compounds of formula I are used for the above-mentioned uses, they can be combined with one or more pharmaceutically acceptable carriers, e.g. solvents, diluents, and the like, and may be administered orally in this form as tablets, capsules, dispersible powders, granules, suspensions containing e.g. from approx. 0.5 to 5% suspending agent, syrups containing e.g. from approx. 10 to 50% sugar and elixirs containing e.g. from approx. 20 to 50% ethanol and the like, or parenterally in the form of sterile injectable solutions or suspensions containing from ca. 0.5 to 5% suspending agent in an isotonic medium. These pharmaceutical compositions may e.g. contain from approx. 0.5 to approx. 90% active substance combined with carriers, more commonly between 5 and 60% by weight.

The antiatherosclerotic-effective dosage of the active substance used may vary depending on the particular compound used, the mode of administration, and the severity of the disorder being treated. Generally, however, satisfactory results are obtained when the compounds of formula I are administered at a 20 daily dose of from ca. 2 mg to approx. 500 mg / kg body weight, preferably given in divided doses two to four times daily or in a formulated preparation with a contraceptive effect. For most large mammals, the total daily dose ranges from approx. 100 to approx.

5000 mg, preferably from ca. 100 to 2000 mg. Dosage forms suitable for internal use comprise from ca. 25 to 500 mg of active compound in intimate admixture with a solid or liquid pharmaceutically acceptable carrier. The dosage can be adjusted to obtain the optimal therapeutic response. Thus, multiple sub-doses may be administered daily or the dose may be reduced proportionally as required in the therapeutic situation.

A definite practical advantage is that these active compounds can be administered orally and by intravenous, intramuscular or subcutaneous route, 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, peanut and sesame oil,

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depending on the nature of the active substance and the particular mode of administration desired. Excipients commonly used in the manufacture of pharmaceutical compositions may be successfully included such as flavoring agents, colorants, preservatives 5 and antioxidants, e.g. vitamin E, ascorbic acid, BHT and BHA.

The preferred pharmaceutical compositions for ease of preparation and administration are solid compositions, especially tablets and hard or liquid filled capsules. Oral administration of the compound is preferred.

These active compounds may also be administered parenterally or intraperitoneally. Solutions or suspensions of these active compounds as a free base or a pharmaceutically acceptable salt can be prepared in water, suitably mixed with a surfactant such as hydroxypropyl cellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols and mixtures thereof in oils. Under general storage and use conditions, these preparations contain a preservative to prevent the growth of microorganisms.

The pharmaceutical forms suitable for injection use include sterile aqueous solutions or dispersions and sterile powders for the preparation of ordered sterile injectable solutions or dispersions. In all cases, the mold must be sterile and must be liquid to such an extent that they can be readily administered by syringe. It must be stable under manufacturing and storage conditions and must be preserved against the pollutant effects of microorganisms such as bacteria and fungi. The carrier may be a solvent or dispersion medium containing e.g. water, ethanol-gOol, polyol (e.g., glycerol, propylene glycol and liquid polyethylene glycol), its oblique mixers, and vegetable oils.

The method according to the invention will be explained in more detail by way of example.

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Example 1 1-Benzyl-1- (n-butyl) -3,3-diphenylurea A solution of 20.0 g of phosgene in 100 ml of toluene is stirred at 0 ° C while a solution of 32.6 g of N-benzyl-n -butylamine 5 in 50 ml of toluene is added over 15 minutes. The mixture is filtered and the filtrate is evaporated. The residue is distilled for evaporation at 105 ° C under reduced pressure (250-250 u) to give N-benzyl-N- (n-butyl) carbamyl chloride as a colorless liquid.

A solution of 3.89 g of diphenylamine in 25 ml of dimethyl acetamide is added over an 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 nitrogen atmosphere at 45-50 ° C. The mixture is stirred for 2 hours at 50 ° C and then poured into water. The mixture is extracted with methylene chloride and the extract is evaporated. The residue is purified by chromatography using silica gel as adsorbance and acetone / hexane and eluent.

After evaporation of the eluent, the residue is distilled for evaporation at 165 ° C under reduced pressure (150 µl) to give 1-benzyl-1- (n-butyl) -3,3-diphenylurea as a viscous, clear, colorless liquid.

Example 2 1-Benzyl-1- (n-butyl) -3- (3-chlorophenyl) -3-phenylurea 25 A solution of 5.09 g of N-phenyl-3-chloroaniline in 20 ml of toluene is added to a solution of 4 , 70 g of phosgene and 3.64 g of Ν, Ν-dimethylaniline in 55 ml of toluene and the mixture is heated to 40 ° C and then stirred under cooling to room temperature over 45 minutes. The mixture is extracted with water and the organic layer is separated and evaporated to ca. half its volume. To this solution is added 100 ml of toluene followed by 9.80 g of N-benzyl-n-butylamine. The resulting mixture is stirred at reflux for 30 minutes and then washed with water, 1N hydrochloric acid and saturated sodium bicarbonate solution. The organic layer is separated, dried over sodium sulfate, decolorized with activated charcoal and evaporated. The residue is distilled for evaporation at 185-190 ° C under reduced pressure (105

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provides the title compound as a viscous, pale yellow liquid.

The compounds in the table below are prepared from appropriate amines by means of hosgene and thiophosgene as described in Examples 1 and 2.

Table II

Ex. Forbindelse_Smeltep.

3 1,3-Dibenzyl-1- (n-butyl) -3-phenylurea yellow oil 4 1-Benzyl-1- (n-butyl) -3- (2-naphthyl) -3-phenylurea orange oil 5 1-Benzyl-1- (n-butyl) -3- (3-methylphenyl) -3- -phenylurea oil 6 1-Benzyl-1- (n-butyl) -3- (4-isopropylphenyl) -3-amber - (4-isopropylphenyl) -3-phenylurea oil 7 1-Benzyl-1- (n-butyl) -3- (3-methoxyphenyl) -3-phero-colored nylurea oil 8 1-Benzyl-1- (n-butyl ) -3- (3-chlorophenyl) -3- (2-naphthyl) urea yellow oil 9 9-Benzyl-1- (n-butyl) -3- (1-naphthyl) -3-phero-colored nylurea oil 1-Benzyl-1- (n-butyl) -3,3-dibenzylurea yellow oil 11 1-Benzyl-1- (n-butyl) -3,3-di (2-naphthyl) urea amber oil 12 Benzyl-1- (n-butyl) -3-benzyl-3- (4-chlorophenyl) urea oil 13 1-Benzyl-1- (n-butyl) -3-benzyl-3- (2,4-dimethyl) phenyl) urea oil 14 1-Benzyl-1- (n-butyl) -3-benzyl-3- (2,4-dichlorophenyl) urea oil 1-Benzyl-1- (n-butyl) -3- (3-Nitrobenzyl) -3- (3,5-dimethoxyphenyl) urine oil 16 1-Benzyl-1- (n-butyl) -3- (2,4-dimethylbenzyl) -3- (2,4-dimethylbenzyl) diphenyl l) Urea oil 1 17-Benzyl-1- (n-butyl) -3- (2,4-dichlorobenzyl) -3- (2,4-dichlorophenyl) urea oil

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Table II (continued)

Ex. Compound Melting point 18 1-Benzyl-1- (n-butyl) -3- (2-chlorobenzyl) -3- (2-chlorophenyl) urea oil 5 19 1-Benzyl-1- (n-butyl) -3- (4) -methylphenyl) -3- (4-methylbenzyl) urea oil 1-Benzyl-1- (n-butyl) -3- (2,4-dimethylbenzyl) -3- (2,4-dichlorophenyl) urea oil 21 1-Benzyl-1- (n-butyl) -3- (2,4-dichlorobenzyl) -3- (2,4-dimethylphenyl) urea oil 22 1-Benzyl-1- (n-butyl) -3- (3-Chloro-4-methylbenzyl) -3- (4-methylphenyl) urea oil 23 1-Benzyl-1- (n-butyl) -3- (2,4-dimethylbenzyl) -3-phenylurea oil 24 1-Benzyl-1- (n-butyl) -3- [3,5-di (trifluoromethyl) benzyl] -3-phenylurea oil 1-Benzyl-1- (n-butyl) -3- (3 aminobenzyl) -3- (3,5-

(dimethoxyphenyl) urea picrate 156-158 ° C

26 1-Benzyl-1- (n-butyl) -3-benzyl-3- (3-aminophe-

Nyl) 96-98 ° C

27 1-Benzyl-1- (n-butyl) -3-benzyl-3- (2,4,6-trimethyl)

thylphenyl) urea 63-69 ° C

28 1-Benzyl-1- (n-butyl) -3-benzyl-3- (3-nitrophenyl) urea yellow oil 29 1-Benzyl-1- (n-butyl) -3-benzyl-3- ( 3-acetamido-phenyl) urea oil

Example 30 N- (2,4-Dimethylbenzylidene) -2,4-dichloroaniline (starting compound) A mixture of 26.8 g of 2,4-dimethylbenzaldehyde, 32.4 g of 2,4-dichloroaniline, 0.20 g of p toluene sulfonic acid and 150 ml of toluene are stirred under reflux using a Dean-Stark humidity trap. Evaporation of the mixture gives a solid which is recrystallized from ethanol to give the title compound, mp 102-106 ° C.

Anilines prepared by the above method are listed in the table below.

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Table III

Ex. Compound (starting compound) Melting point 31 N-Benzylidene-2,4,6-trimethylaniline yellow oil

32 N-Benzylidene-2,4-dichloroaniline 0-6 ° C

33 N- (4-Methylbenzylidene) -3-chloro-4-methyl-

aniline 86-89 ° C

34 N- (2,4-Dimethylbenzylidene) -2,4-dimethyl

aniline 118-121 ° C

N- (2,4-Dichlorobenzylidene) -2,4-dimethyl

10 aniline 105-107 ° C

36 N- (3-Nitrobenzylidene) -3,5-dimethoxyaniline 113-116 ° C

37 N-Benzylidene-4-chloroaniline 60-62 ° C

38 N-Benzylidene-2,4-dimethylaniline oil

39 N- (2,4-Dichlorobenzylidene) -2,4-dichloroaniline 134-139 ° C

N- (2-Chlorobenzylidene) -2-chloroaniline 111-117 ° C

41 N- (4-methylbenzylidene) -4-methylaniline 90-93 ° C

42 N-Benzylidene-3,5-di (trifluoromethyl) aniline yellow oil 43 N- (4-Benzyloxybenzylidene) -4-carboethoxy

aniline 140-142 ° C

44 N-Benzylidene-3-nitroaniline 69-72 ° C

Example 45 N- (2,4-Dimethylbenzyl) -2,4-dichloroaniline (starting compound)

A mixture of 13.9 g of N- (2,4-dimethylbenzylidene) -25 -2,4-dichloroaniline, 1.89 g of sodium borohydride and 150 ml of ethanol is stirred at reflux for one hour, allowed to cool and poured into water. . Recrystallization from ethanol gives N- (2,4-dimethylbenzyl) -2,4-dichloroaniline, m.p. 88-90 ° C.

Anilines prepared by the above process 30 are listed in Table VI.

Table IV

Ex. Compound Melting point 46 N-Benzyl-2,4,6-trimethylaniline oil 47 N-Benzyl-2,4-dichloroaniline oil 48 N- (4-Methylbenzyl) -3-chloro-4-methylaniline oil

49 N- (2,4-Dimethylbenzyl) -2,4-dimethylaniline 72-74 ° C

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Table IV (cont.)

Ex. Forbindelse_Smeltepunkt

N- (2,4-Dichlorobenzyl) -2,4-dimethylaniline 70-72 ° C

51 N- (3-Nitrobenzyl) -3,5-dimethoxyaniline amber oil

52 N-Benzyl-4-chloroaniline 48-49 ° C

53 N-Benzy1-2,4-dimethylaniline 28-33 ° C

54 N- (2,4-Dichlorobenzyl) -2,4-dichloroaniline 84-86 ° C

55 N- (2-Chlorobenzyl) -2-chloroaniline 41-44 ° C

56 N- (3-Methylbenzyl) -4-methylaniline 50-54 ° C

57 N-Benzyl-3,5-di (trifluoromethyl) aniline oil

58 N- (4-Benzyloxybenzyl) -4-carboethoxyaniline 147-150 ° C

59 N-Benzyl-3-nitroaniline 106-108 ° C

Example 60 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 is added to a solution of 4.41 g of N-benzyl-1- (n-butyl) amine, m.p. 70-71 ° C.

The compounds in the table below are prepared from 20 suitable arylisocyanates or arylisothiocyanates and secondary amines by the method described in Example 60 above.

Table V

Ex ♦ Connection_Melting Point

61 1-Benzyl-1- (n-butyl) -3- (2-methylphenyl) urea 48-53 ° C

62 1-Benzyl-1- (n-butyl) -3- (3-methylphenyl) urea 91-92 ° C

63 1-Benzyl-1- (n-butyl) -3- (4-methylphenyl) urea 102-103 ° C

6 4 1-Benzyl-1- (n-butyl) -3- (2,3-dimethylphenyl) urea 77-78 ° C

65 1-Benzyl-1- (n-butyl) -3- (2,5-dimethylphenyl) -

urea 87-89 ° C

66 1-Benzyl-1- (n-butyl) -3- (2,6-dimethylphenyl) -

urea 125-126 ° C

67 1-Benzyl-1- (n-butyl) -3- (3,4-dimethylphenyl) -

Urea 94-95 ° C

68 1-Benzyl-1- (n-butyl) -3- (3,5-dimethylphenyl) -

urea 108-109 ° C

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Table V (continued)

Ex. Compound Melting Point 69 1-Benzyl-1- (n-butyl) -3- (2,4,6-trimethyl)

phenyl) urea 141-144 ° C

70-1-Benzyl-1- (n-butyl) -3- (3,4,5-trimethoxy)

phenyl) urea 144-145 ° C

71 1-Benzyl-1- (n-butyl) -3- (3,4-dichlorophenyl) -

urea 102-105 ° C

72 1-Benzyl-1- (n-butyl) -3- (3,5-dichlorophenyl) τ

10 urea 100-103 ° C

73 1-Benzyl-1- (n-butyl) -3- (3-trifluoromethyl) -

-phenyl) urea 86-87 ° C

74 1-Benzyl-1- (n-butyl) -3- (3-chloro-2-methoxy-

phenyl) urea 52-54 ° C

75 1-Benzyl-1- (n-butyl) -3- (5-chloro-4-methoxyphenyl)

nyl) 61-63 ° C

76 1-Benzyl-1- (n-butyl) -3- (3-chloro-4-methylphenyl) urea yellow oil 77 1-Benzyl-1- (1,2-diphenylethyl) -3- (2.4 -dime-

Thylphenyl) urea 157-158 ° C

78 1-Benzyl-1- [1- (3-methoxyphenyl) -2-phenyl]

ethyl] -3- (2,4-dimethylphenyl) urea 124-126 ° C

79 1-Benzyl-1- [1- (4-benzyloxyphenyl) -2-phe-

nylethyl] -3- (2,4-dimethylphenyl) urea 140-141 ° C

80 1-Benzyl-1- [1- (3-methoxyphenyl) -2-phenyl]

thyl] -3- (3-trifluoromethylphenyl) urea 125-126 ° C

81 1-Benzyl-1- (n-pentyl) -3- (2,4-dimethylphenyl) urea oil 82 1-Benzyl-1- (n-hexyl) -3- (2,4-dimethylphenyl) urea oil 83 1-Benzyl-1- (n-octal) -3- (2,4-dimethylphenyl) - urea oil 84 1-Benzyl-1- (n-undecyl) -3- (2,4-dimethylphenyl) - urea oil

85 1-Benzyl-1- (n-butyl) -3- (3-phenyl) thiourea 83-85 ° C

86 1-Benzyl-1- (n-butyl) -3- (3-chloro-2-methoxyphenyl)

nyl) urea 52-54 ° C

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Table V (continued)

Ex. Compound Melting point 87 1-Benzyl-1- (n-butyl) -3- (5-chloro-2-methoxy)

phenyl) urea 161-163 ° C

88 1- (n-Butyl) -1- (2-fluorobenzyl) -3- (2,4-dimethyl)

phenyl) urea 76-77 ° C

'89 1- (n-Butyl) -1- (4-fluorobenzyl) -3- (2,4-dime)

thylphenyl) urea 78-79 ° C

.90 1- (n-Butyl) -1- (2-chlorobenzyl) -3- (2,4-dimethyl)

1Q thylphenyl) urea 101-102 ° C

91 1- (n-Butyl) -1- (2,6-dichlorobenzyl) -3- (2,4-di-

methylphenyl) urea 145-146 ° C

9.2 1- (4-Bromobenzyl) -1- (n-butyl) -3- (2,4-dimethyl)

thylphenyl) urea 61-63 ° C

93 1- (n-Butyl) -1- (4-n-butylbenzyl) -3- (2,4-dimethyl) benzyl

thylphenyl) urea 60-62 ° C

94 1- (n-Butyl) -1- (4-methylbenzyl) -3- (2,4-dimethylphenyl) urea oil 95 1- (n-Butyl) -1- (4-tert-butylbenzyl) - 3 "(2,4-

20-dimethylphenyl) urea 28-31 ° C

96 1- (n-Butyl) -1- (4-chlorobenzyl) -3- (2,4-dimethylphenyl) urea oil 97 1- (n-Butyl) -1- (4-methoxybenzyl) -3- ( 2,4-dimethylphenyl) urea oil 98 1- (n-Butyl) -1- (3,4-methylenedioxybenzyl) -3- (2,4-dimethylphenyl) urea oil 99 1- (n-Butyl) -1- (4-trifluoromethylbenzyl) -3- (2,4-dimethylphenyl) urea oil 100 1- (n-Butyl) -1- (4-phenylbenzyl) -3- (2,4-dimethyl) benzyl

Thylphenyl) urea 82-83 ° C

101 1- (n-Butyl) -1- (2-phenylethyl) -3- (2,4-dimethylphenyl) urea oil 102 1- (n-Butyl) -1- [2- (4-fluorophenyl) ethyl ] -3- - (2,4-dimethylphenyl) urea oil 103 1- (n-Butyl) -1- [2- (4-chlorophenyl) ethyl] -3- - (2/4-dimethylphenyl) urea oil

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Table V (continued)

Ex. Compound Melting point 104 1- (n-Butyl) -1- [2- (3-methoxyphenyl) ethyl] -3- (2,4-dimethylphenyl) urea oil 105-1- (n-Butyl) -1- (3- phenylpropyl) -3- (2,4-dimethylphenyl) urea oil

106 1- (n-Butyl) -1- [4- (n-pentyl) benzyl] -3- (2,4-dimethylphenyl) urea 65-67 C

107 1- (n-Butyl) -1- [4- (n-hexyl) benzyl (-3- (2,4-dimethylphenyl) urea oil 108 1- (n-Butyl) -1- (3 Chlorobenzyl) -3- (2,4-dimethylphenyl) urea oil 109 1- (n-Butyl) -1- [4- (n-butoxy) benzyl] -3- (2,4- dimethylphenyl) urea oil 110 1- (n-Butyl) -1- [4- (n-pentyloxy) benzyl] -3- (2,4- -dimethylphenyl) urea oil 111 1- (n-Butyl) -1- [4- (n -hexyloxy) benzyl] -3- (2,4- -dimethylphenyl) urea oil 112 1- (n-Butyl) -1- [4- (n-heptyloxy) benzyl] -3- (2,4-dimethylphenyl) ) urea oil 113 1- (n-Butyl) -1- (4-nitrobenzyl) -3- (2,4-dimethylphenyl) urea oil 114 1- (n-Butyl) -1- [2- (2-methylphenyl) ethyl] -3-

- (2,4-dimethylphenyl) urea 102-103 ° C

115 1- (n-Butyl) -1- [2- (3-methylphenyl) ethyl] -3- - (2,4-dimethylphenyl) urea oil 116 1- (n-Butyl) -1- [2- ( 4-methylphenyl) ethyl] -3- - (2,4-dimethylphenyl) urea oil 117 1- (n-Butyl) -1- [2- (4-methoxyphenyl) ethyl] -3- (2,4- dimethylphenyl) urea oil 118 1- (n-Butyl) -1- [2- (3-fluorophenyl) ethyl] -3- - (2,4-dimethylphenyl) urea oil 119 1- (n-Butyl) -1- [ 2- (2-chlorophenyl) ethyl] -3- - (2-4-dimethylphenyl) urea oil 120 1- (n-Butyl) -1- [2- (3-chlorophenyl) ethyl] -3- - (2 , 4-dimethylphenyl) urea oil

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Table V (continued)

Ex. Compound Melting point 121 '1- (n-Butyl) -1- [2- (3-bromophenyl) ethyl] -3- - (2,4-dimethylphenyl) urea oil 122 1- (n-Butyl) -1- [2 - (3,4-methylenedioxyphenyl) ethyl] -3- (2,4-dimethylphenyl) urea oil

123 1- (n-Butyl) -1- (2-adamantylethyl) -3- (2,4-dimethylphenyl) urea 134-135 ° C

124 1- (n-Butyl) -1- (α-cyclohexylbenzyl) -3- (2,4-

10-dimethylphenyl) urea 112-113 ° C

125 1- (n-Butyl) -1- (di- (4-chlorophenyl) methyl) -3-

- (2,4-dimethyl) -3- (2,4-dimethylphenyl) urea 145-147 ° C

126 1- (n-Butyl) -1- (3,4-dichlorobenzyl) -3- (2.4-

15-dimethylphenyl) urea 120-212 ° C

127 1- (n-Butyl) -1- (3-trifluoromethylbenzyl) -1- (4-fluorobenzyl) -3- (2,4-dimethylphenyl) -

urea 114-115 ° C

128 1- (4-Chlorobenzyl) -1- (1-naphthylmethyl-3-

20 - (2,4-dimethylphenyl) urea 134-136 ° C

129 1- (4-Methoxybenzyl) -1- (2,4-dichlorobenzyl) -

-3- (2,4-dimethylphenyl) urea 124-126 ° C

130 1- (3-Chlorobenzyl) -1- (4-methoxybenzyl) -3-

- (2,4-dimethylphenyl) urea 108-109 ° C

131 1- (4-Phenylbenzyl) -1- (3,4-dichlorobenzyl) -

-3- (2,4-dimethylphenyl) urea 103-105 ° C

132 1- (4-Fluorobenzyl) -1- (4-methylbenzyl) -3-

- (2,4-dimethylphenyl) urea 128-130 ° C

133 1- (4-Chlorobenzyl) -1- (3,4-dimethylbenzyl) -

-3- (2,4-dimethylphenyl) urea 94-96 ° C

134 (1- (4-Fluorobenzyl) -1- (3,4-methylenedioxybenzene)

yl) -3- (2,4-dimethylphenyl) urea 122-124 ° C

1- (n-Butyl) -1- (4-methylthiobenzyl) -3- (2,4- dimethylphenyl) urea oil 136 1- (2,4-Dichlorobenzyl) -1- (4-methylthiobenzyl)

yl) -3- (2,4-dimethylphenyl) urea 124-125 ° C

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Table V (continued)

Ex. Compound Melting point 137 1- [2- (3,4-Dimethoxyphenyl) ethyl] -1- (3,4-methylenedioxybenzyl) -3- (2,4-dimethylphenyl) urea oil 138 1- [2- ( 2-Methylphenyl) ethyl] -1- (2,4-dichloro-

benzyl) -3- (2,4-dimethylphenyl) urea 120-122 ° C

139 1- [2- (4-Methylphenyl) ethyl] -1- (4-chlorobenzyl) -3- (2,4-dimethylphenyl) urea oil 140 1- [2- (4-Ethoxyphenyl) ethyl] - 1- (2-Chlorobenzyl) -3- (2,4-dimethylphenyl) urea oil 141 1- [2- (3-Fluorophenyl) ethyl] -1- (3-methoxybenzyl) benzyl

yl) -3- (2,4-dimethylphenyl) urea 94-95 ° C

142 1- [2- (3-Methoxyphenyl) ethyl] -1- (2-chlorobenzene)

(Yl) -3- (2,4-dimethylphenyl) urea 73-74 ° C

1- (3,3-Diphenylpropyl) -1- (4-fluorobenzyl) -3-

- (2,4-dimethylphenyl) urea 109-110 ° C

144 1- (n-Butyl) -1- (3,3-diphenylpropyl) -3- (2.4-

(dimethylphenyl) urea 94-95 ° C

145 1- (n-Butyl) -1- (4-cyclohexylbutyl) -3- (2,4-dimethylphenyl) urea oil 146 1- [2- (3,4-Dimethoxyphenyl) ethyl] -1- ( 3-Chloro-4-methylbenzyl) -3- (2,4-dimethylphenyl) urea gum 147 1- [2- (2-Methylphenyl) ethyl] -1- (4-bromobenzyl)

(1-yl) -3- (2,4-dimethylphenyl) urea 126-127 ° C

148 1- [2- (3-Trifluoromethylphenyl) ethyl] -1- (2-

-chlorobenzyl) -3- (2,4-dimethylphenyl) urea 115-117 ° C

149 1- (2-Fluorobenzyl) -1- (2-methoxybenzyl) -3- (2.4-

-dimethylphenyl) urea 96-98 ° C

150 1- [2- (3,4-Dimethoxyphenyl) ethyl] -1- (4-fluorobenzyl) -3- (2,4-dimethylphenyl) urea rubber 151 1- [2- (4-Ethoxyphenyl) ethyl ] -1- (2,4-dimethylbenzyl) -3- (2,4-dimethylphenyl) urea rubber 152 1- [2- (3-Methylphenyl) ethyl] -1- (3-nitrobenzyl) -

-3- (2,4-dimethylphenyl) urea 99-101 ° C

1- [2- (2,5-Dimethoxyphenyl) ethyl] -1- (3-chloro)

benzyl) -3- (2,4-dimethylphenyl) urea 86-88 ° C

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Table V (continued)

Ex. Compound Melting point 154 1- (n-Butyl) -1- (2-methyl-2,2-diphenyl)

thyl-3- (2,4-dimethylphenyl) urea 159-160 ° C

155- (n-Butyl) -1- (4-hexoxyloxybenzyl) -3- (2,4,6-

-trimethylphenyl) urea 90-91 ° C

156 1- (n-Butyl) -1- (4-heptyloxybenzyl) -3- (2,4,6-

-trimethylphenyl) urea 86-87 ° C

157 1- (n-Butyl) -1-benzyl-3- (4-trifluoroacetylamide)

-10 no-3,5-dichlorophenyl) urea 173-175 ° C

158 1-Benzyl-1- (4-n-butylbenzyl) -3- (2,4-dimethylphenyl) urea oil 159 1-Benzyl-1- (4-n-butylbenzyl) -3- (2,4,6- tri-ethylphenyl) urea oil 160 160 1-Benzyl-1- (4-n-butylbenzyl) -3- (4-n-butylphenyl) urea yellow oil

161 1-Benzyl-1- (4-n-butylbenzyl) -3- (4-phenoxyphenyl) urea 79-80 ° C

162 1- (n-Heptyl) -1- (4-n-butylbenzyl) -3- (2,4-dimethylphenyl) urea yellow oil 163 1- (n-Hepthyl) -1- (4- n-butylbenzyl) -3- (2,4,5-trimethylphenyl) urea yellow oil 164 1-Benzyl-1- [2-phenyl-1- (4-benzyloxyphenyl) -

ethyl] -3- (2,4, 5-trimethylphenyl) urea 157-158 ° C

165 1- (n-Heptyl) -1- (4-butyloxybenzyl) -3- (2,4-dimethylphenyl) urea oil 166 1- (n-Heptyl) -1- (4-butyloxybenzyl) -3- (2,4,5-trimethylphenyl) urea yellow oil 167 1-Benzyl-1- (4-butyloxybenzyl) -3- (2,4-dimethylphenyl) urea solid 168 1-Benzyl-1- (4- butyloxybenzyl) -3- (2,4,5-trimethylphenyl) urea solid 169 1- (9-Octadecenyl) -1- (4-n-butylbenzyl) -3- (2,4- dimethylphenyl) urea yellow oil 170 1-Benzyl-1- (4-n-butylbenzyl) -3- (2,4,5-trimethylphenyl) urea yellow oil

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Table V (cont.)

Ex. Compound Melting point 171 1- (9-Octadecenyl) -1- (4-n-butylbenzyl) -3- - (2,4,5-trimethylphenyl) urea yellow oil 172 1-Benzyl-1- [2-phenyl] -1- (4-benzyloxy-phenyl) -

ethyl] -3- (2,4,6-trimethylphenyl) urea 140-141 ° C

173 1- (n-Heptyl) -1- (4-n-butoxybenzyl) -3- (2,4,6-

-trichlorophenyl) urea 63-64 ° C

174 1- (n-Heptyl) - (4-n-butoxybenzyl) -3- (2,4-dichlorophenyl) urea rubber 175 1- (n-Heptyl) - (4-n-butoxybenzyl) -3- (2-trifluoromethyl-3-chlorophenyl) urea gum 176 1-Benzyl-1- (4-n-butoxybenzyl) -3- (2,4,6-trifluoromethyl) benzyl

chlorophenyl) urea 91-93 ° C

177 1-Benzyl-1- (4-n-butoxybenzyl) -3- (2,4-dichlorophenyl) urea rubber 178 1-Benzyl-1- (4-n-butoxybenzyl) -3- (2-trifluoro - methyl) -4-chlorophenyl) urea rubber 179 1- (n-Heptyl) -1- (4-n-butoxybenzyl) -3- (3-trifluoromethylphenyl) urea rubber 180 1- (n-Benzyl) - 1- (4-n-butoxybenzyl) -3- (3-trifluoromethylphenyl) urea rubber 181 1- (n-Heptyl) -1- (4-n-butylbenzyl) -3- (2,4-dichlorophenyl) ) urea rubber 182 1- (n-Heptyl) -1- (4-n-butylbenzyl) -3- (2-trifluoromethyl-4-chlorophenyl) urea rubber 183 1- (n-Heptyl) -1- ( 4-n-butylbenzyl) -3- (2,4,6-trichlorophenyl) urea gum 184 1- (n-Heptyl) -1- (4-n-butylbenzyl) -3- (3-trifluoromethylphenyl) Urea Rubber 185 1- (n-Heptyl) -1- (4-n-butylbenzyl) -3- (2,4,5- -trichlorophenyl) Urea Rubber 186 1-Benzyl-1- (4-n-butylbenzyl) - 3- (2-methyl-4-

(chlorophenyl) urea 107-108 ° C

1- (n-Heptyl) -1- (4-n-butoxybenzyl) -3- (2,4-difluorophenyl) urea gum

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Table V (continued). Ex. Compound Melting point 188 1- (n-Heptyl) -1- (4-n-butoxybenzyl) -3- (2-methyl-4-chlorophenyl) urea gum 1- (n-Heptyl) -1- ( 2-furyl) -3- (2,4,5-trimethyl

thylphenyl) urea 65-67 ° C

190 1- (n-Heptyl) -1- (2-furyl) -3- (2,4,6-trichlorophenyl) urea yellow oil 191 1- (n-Heptyl) -1- (4-n-bitylbenzyl) ) -3- (2-methyl-10-4-chlorophenyl) urea oil 192 1- (n-Heptyl) -1- (4-n-butylbenzyl) -3- (2,4-difluorophenyl) urea oil 193 L- (n-heptyl) -L- (4-n-Butyl-benzyl) -3- (4-carbo-

ethoxyphenyl) urea 65-66 ° C

1- (n-Heptyl) -1- (4-n-butylbenzyl) -3- (2-methylphenyl) urea oil 195 1- (n-Heptyl) -1- (4-n-butylbenzyl) - 3- (3-methylphenyl) urea oil 196 1- (n-Heptyl) -1- (4-n-butylbenzyl) -3- (4-carb)

Phenyl) urea 147-149 ° C

1- (n-Heptyl) -1- (2-phenylethyl) -3- (2-methyl-4-chlorophenyl) urea rubber 198 1- (n-Heptyl) -1- (2-phenylethyl) -3 - (2,4,5-trichlorophenyl) urea gum 199 1- (n-Heptyl) -1- (2-phenylethyl) -3- (2-trifluoromethyl-4-chlorophenyl) urea gum 200 1- (n-Heptyl) -1- (2-phenylethyl) -3- (2,4-dimethylphenyl) urea rubber 201 1- (n-Heptyl) -1- (2-phenylethyl) -3- (2.4 -dichlorophenyl) urea gum 202 1- (n-Heptyl) -1- (2-phenylethyl) -3- (2,4-difluorophenyl) urea gum 203 1- (n-Heptyl) -1- ( 2-phenylethyl) -3- (3-trifluoromethylphenyl) urea rubber 204 l-Benzyl-1- [2-phenyl-1- (4-benzyloxyphenyl) -

ethyl] -3- (2,4,6-trichlorophenyl) urea 131-133 ° C

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33

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Table V (continued)

Ex. Compound Melting point 205 1- (4-n-Pentylbenzyl) -1- (4-n-pentyloxybenzyl) -3- (2,4,6-trichlorophenyl) urea oil 206 1- (4-n-Pentylbenzyl) -1 - (4-n-pentyloxybenzyl) -3- (2,4-dichlorophenyl) urea oil 207 1- (4-n-Pentylbenzyl) -1- (4-n-pentyloxybenzyl) -3- (2, 4,5, trichlorophenyl) urea oil 208 1- (4-n-Pentylbenzyl) -1- (4-n-pentyloxybenzyl) -3- (2-trifluoromethyl-4-chlorophenyl) - urea oil 209 1- ( 4-n-Pentylbenzyl) -1- (4-n-pentyloxybenzyl) -3- (3-trifluoromethylphenyl) urea oil 210 1- (4-n-Pentylbenzyl) -1- (4-n-pentyloxybenzyl) ) -3- (2,4-difluorophenyl) urea oil 211 1- (4-n-Pentylbenzyl) -1- (4-n-pentyloxybenzyl) -3- (2-methyl-4-chlorophenyl) urea oil 212 1- (4-Chloro-benzyl) -1- (1-naphthylmethyl (-3-

- (2,4,6-trichlorophenyl) urea 157-159 ° C

213 1- (4-Chlorobenzyl) -1- (1-naphthylmethyl) -3-

- (2-methyl-4-chlorophenyl) urea 168-169 ° C

214 1- (4-Chlorobenzyl) -1- (1-naphthylmethyl) -3-

- (2,4-difluorophenyl) urea 122-124 ° C

215 1- (4-Chlorobenzyl) -1- (1-naphthylmethyl) -3-

25 - (3-trifluoromethylphenyl) urea 127-129 ° C

216 1- (4-Chlorobenzyl) -1- (1-naphthylmethyl) -3-

- (2,4,5-trichlorophenyl) urea 110-113 ° C

217 1-Benzyl-1- [2-phenyl-1- (4-benzyloxyphenyl) -

-ethyl] -3- (2,4., 5-trichlorophenyl) urea 142-145 ° C

218 1-Benzyl-1- (4-n-butyloxybenzyl) -3- (2,4,5-trichlorophenyl) urea oil 219 1-Benzyl-1- [2-phenyl-1- (4-benzyloxyphenyl) -

ethyl] -3- (2,4-difluorophenyl) urea 84-85 ° C

220 1-Benzyl-1- (4-n-butoxybenzyl) -3- (2,4-difluorophenyl) urea oil 221 1-Benzyl-1- [2-phenyl-1- (4-benzyloxyphenyl) -

ethyl] -3- (2,4-difluorophenyl) urea 126-128 ° C

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Table V (continued)

Ex. For example, melting point 222 1-Benzyl-1- [2-phenyl-1- (4-benzylpxyphenyl) ethyl] -3- (2-trifluoromethyl-4-chlorophenyl) -

5 urea 99-101 ° C

223 1-Benzyl-1- [2-phenyl-1- (4-benzyloxyphenyl) -

ethyl] -3- (3-trifluoromethylphenyl) urea 102-104 ° C

224 1-Benzyl-1- [2-phenyl-1- (4-benzyloxyphenyl) -

ethyl] -3- (2-methyl-4-chlorophenyl) urea 125-126 ° C

225 1- (4-Chlorobenzyl) -1- (1-naphthylmethyl) -3-

- (2,4-dichlorophenyl) urea 96-98 ° C

226 1- (4-Chlorobenzyl) -1- (1-naphthylmethyl) -3- - (2-trifluoromethyl-4-chlorophenyl) urea yellow glass Example 227 1-Benzyl-1- (n-butyl) -3- ( 3-chlorophenyl) urea

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

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

30

Example 228 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 is treated with 25 ml of 35 IN aqueous sodium hydroxide, stirred at reflux for 16 hours, allowed to cool, acidify with 1N hydrochloric acid and filter.

The solid is recrystallized from ethanol to give

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the title mentioned as a white solid.

Example 229 1-Benzyl-1- (n-butyl) -3 "(2-hydroxy-3-chlorophenyl) urea A solution of 1.73 g of 1-benzyl-1- (n-butyl) -3- (2) - methoxy-3-chlorophenyl) urea and 1.00 ml boron tribromide in 40 ml methylene chloride are stirred at ambient temperature for 3 days and diluted with water. The organic layer is separated, dried and evaporated. The residue is crystallized from hexane to give 10 above the title compound, mp 59-62 ° C.

Example 230 N- (2-chlorobenzyl) -3-methoxyphenylacetamide (starting compound)

A mixture of 12.5 g of 3-methoxyphenylacetic acid, 21.2 15 g of 2-chlorobenzylamine, 15.1 g of triethylamine, 19.3 ml of boron trifluoride etherate and 500 ml of toluene is stirred at reflux for 18 hours using a Dean - Strong appliance and allowed to cool. The mixture is extracted with aqueous sodium hydroxide, dilute hydrochloric acid and water. The remaining organic solution is then evaporated and the residue is crystallized from hexane to give the title compound as a yellow solid, mp 89-91 ° C.

Example 231 N- (n-Butyl) -2-chlorobenzylamine (starting compound)

A solution of 21.2 g of N- (n-butyl) -3-chlorobenzamide in 100 ml of tetrahydrofuran is added with cooling to 200 ml of 1 molar borane in tetrahydrofuran and the mixture is stirred at reflux for 18 hours, allowed to cool and treated with 6N 30 hydrochloric acid. The organic solvent is evaporated and the residue partitioned between ether and aqueous sodium hydroxide solution. The ether layer is separated, dried and evaporated. The residue is distilled to give the title compound as a colorless liquid, boiling point 65-75 ° C at 60 ° C.

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36

Example 232 3- (2,4-Difluorophenyl) -1- [4- (2,2-dimethylpropyl) phenyl] methyl-1H-1-heptylurea

A solution of 6.73 g of neopentylbenzoic acid and 13.0 5 ml of thionyl chloride in 40 ml of dichloromethane is heated to reflux for 4 hours. The reaction mixture is cooled and the solvent is evaporated in vacuo. The residue is dissolved in dichloromethane and then evaporated again. This step is repeated again to give neopentyl benzoyl chloride as a brown oil.

This product is dissolved in 40 ml of dichloromethane and added with stirring to a cold solution of 4.04 g of heptylamine and 9.8 ml of triethylamine in 60 ml of dichloromethane. The resulting mixture is stirred at room temperature for 16 hours. Then, the mixture is diluted with water and divided into two layers.

The organic layer is washed successively with twice 30 ml of 3N hydrochloric acid and then with brine. The solution is dried over anhydrous magnesium sulfate and filtered. The filtrate is evaporated in vacuo to give 13.0 g of a gray solid. The solid 20 is purified by preparative high pressure liquid chromatography on silica gel using a mixture of ethyl acetate and hexane in the ratio of 1: 9 as solvent. Fractions 2, 3, 4 and 5 are combined and evaporated in vacuo to give 8.0 g of 4- (2,2-dimethylpropyl) -N-heptylbenzamide as a beige solid having a melting point of 58-60 ° C.

A mixture of 7.5 g (0.026 mol) of this amide and 20 ml (0.052 mol) of Vitride T (sodium dihydro-bis (2-methoxy-ethoxy) aluminate (70% solution in toluene)) 80 ml of toluene is refluxed for 4 hours and then cooled to room temperature. The complex is decomposed by the dropwise addition of 40 ml of 2.5N sodium hydroxide solution with stirring for 30 minutes. The mixture is separated into two layers. The organic layer is washed with brine, dried over anhydrous magnesium sulfate and filtered. The filtrate is evaporated to dryness in vacuo to give a yellow oil. Kugelrohr distillation (125 ° C / 0.15 mm Hg) gives 6.45 g (90% yield) of 4- (2,2-dimethylpropyl) -N-heptylbenzene-37

DK 160869 B

methanamine as a colorless liquid.

To a solution of 1.10 g (0.004 mol) of this amine in 15 ml of hexane is added, with stirring, a solution of 0.62 g (0.004 mol) of 2,4-difluorophenylisocyanate in 15 ml of hexane. The resulting mixture is stirred at room temperature for 16 hours. The solvent is evaporated in vacuo to give a colorless oil. Kugelrohr distillation (140-155 ° C / 0.15 mm Hg) gives 1.44 g (yield 84%) of the desired compound as a colorless oil.

10

Example 233 3- (4-Chloro-2,6-dimethylphenyl) -1- [4- (2,2-dimethylpropyl) phenyl] methyl] -1-heptylurea

To a mixture of 300 g (2.48 mol) of 2,6-dimethylaniline, 2.4 l of dichloromethane and 24 ml of ethanol cooled to 5 ° C in an ice bath, anhydrous hydrogen chloride gas is added over a period of 1 hour. temperature is maintained at 4- 11 ° C. Chlorine gas is passed through the mixture for approx. 2 hours while maintaining the temperature of 5-10 ° C, thereby introducing about 20 ° C. 217 g of chlorine. The reaction mixture is assayed several times by thin layer chromatography using a 10: 1 ethyl acetate-hexane solvent system to ensure that the reaction is complete. After complete reaction, the mixture is rinsed with argon gas and then left at room temperature for 16 hours.

The mixture is cooled to 2 ° C and filtered. The precipitate is washed with 250 ml of dichloromethane and then with 1.5 l of ether and then air dried to give 371 g of 4-chloro-2,6-dimethylbenzenamine monohydrochloride.

To a suspension of this monohydrochloride (371 g, 1.93 mol) in 1.5 L of diethyl ether kept at 12-17 ° C in an ice bath, add 1 1 2M sodium acetate solution over 2-3 minutes with vigorous stirring. . The mixture is stirred for 30 minutes and then allowed to separate into layers. The organic layer is washed successively with 1 L of water, 1 L of saturated sodium bicarbonate solution and 1 L of water. The

DK 160869B

38 organic solution is dried over anhydrous sodium sulfate and filtered. Evaporation gives 288.5 g of solid. This solid is recrystallized from 800 ml of petroleum ether to give 229.8 g of 4-chloro-2,6-dimethylbenzenamine as colorless crystals having a melting point of 47-50 ° C.

To a cold solution of 2.47 g (0.0163 mol) of this amine and 2.4 ml (0.0189 mol) of Ν, Ν-dimethylaniline in 80 ml of toluene is added dropwise a solution of 2.56 g (0, 0163 mole) of phenyl chloroformate in 20 ml of toluene. The resulting mixture is stirred at room temperature for 90 minutes and then diluted with water. The mixture is separated into two layers. The organic layer is washed twice with 40 ml of 3N hydrochloric acid and then with brine.

The organic solution is dried over anhydrous magnesium sulfate and filtered. The filtrate is evaporated in vacuo to give a white solid. The solid is recrystallized from a mixture of ethyl acetate and hexane to give 3.8 g of (4-chloro-2,6-dimethylphenyl) -carbamic acid phenyl ester as a white solid, mp 158-160 ° C.

A mixture of 1.11 g (0.004 mol) of this phenyl ester, 1.10 g (0.004 mol) of 4- (2,2-dimethylpropyl) -N-heptylbenzene methanamine (prepared in Example 232) and 30 ml toluene is refluxed for 2 hours. The solution is cooled and washed with twice 30 ml of 1 N sodium hydroxide solution and then with brine. The solution is dried over anhydrous magnesium sulfate and filtered. The filtrate is evaporated in vacuo to give an oil. Kugelrohr distillation (145-155 * 0 / 0.1 mm Hg) gives 1.47 g of a colorless oil which solidifies on standing to give the desired product as a white solid, mp 111-113 ° C.

30

Example 234 1- [4- (2,2-Dimethylpropyl) phenyl] methyl] -1-heptyl-3- (2,4,6 - trifluorophenyl) urea

To a cold solution of 5.3 g (0.0359 mole) of 2.4.6-35 trifluoroaniline and 5.6 ml (5.4 g, 0.044 mole) of Ν, Ν-dimethylaniline in 70 ml of toluene is added dropwise of 5.63 g 39

DK 160869 B

(0.0359 mol) of phenyl chloroformate in 20 ml of toluene. The resulting mixture is stirred at room temperature for 16 hours to give a precipitate. The mixture is diluted with ethyl acetate and water, separating it into two layers. The organic layer is washed 5 with twice 50 ml of 3N hydrochloric acid and then twice with 50 ml of brine. The solution is dried over anhydrous magnesium sulfate and filtered. The filtrate is evaporated in vacuo to give a solid. The solid is triturated with hexane, collected by filtration, washed with hexane and dried to give 8.38 g (2,4,6-trifluorophenyl) -carbamic acid phenyl ester as a white solid, m.p. 127-128 ° C in a yield of 96%.

A mixture of 0.97 g (0.004 mol) of this carbamate derivative, 1.10 g (0.004 mol) of 4- (2,2-dimethylpropyl) -N-heptyl-benzenemethanamine (prepared in Example 232) and 40 ml toluene is refluxed for 2 hours. The resulting mixture is cooled and washed with twice 30 ml of 1 N sodium hydroxide solution and then with brine. The solution is dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to give a pale yellow oil. Kugelrohr distillation (140-150 ° C / -0.08 mm Hg) gives 1.5 g of colorless oil. A 900 mg portion of this oil is redistilled (140-150 ° C / 0.160 mm Hg) to give 500 mg of the desired compound as a colorless oil.

In the following, compounds known from DE Publication No. 2,928,485 (compounds 1 and 2) are compared with compounds of the invention (compounds 3 to 7).

DK 160869 B

ACAT INHIBITION

IC 50 (µM) * 1.

N- [2-chloro-5- (trifluoromethyl) phenyl] -N '- [3-chloro-4-trifluoromethyl) phenyl] urea 5.52 2.

N- [3-chloro-4- (trifluoromethyl) phenyl] -N1 [3- (trifluoromethyl) phenyl] urea </ γ-KH-co-KH-r y-cf_ 3 23.71 30 3.

N '- (2,4-difluorophenyl) -N - [[4- (2,2-dimethyl-propyl) phenyl] methyl] -N-heptyl-urea 40

DK 160869B

IC50 (µM) * 5 4.

N '- (4-Chloro-2,6-dimethylphenyl) -N - [[4- (2,2-dimethylpropyl) phenyl] methyl] -N-heptyl urea 10 <* 3 (ru 4-ch

Cl - 0.24 15 20 5.

N * - (2,4-difluorophenyl) -N-heptyl-N - [[4- (3-methyl-butyl) phenyl] methyl] urea p-V-CH2-CHeHjH-CHj 30 ΜΛ fc1 · 1 35 6th

N-heptyl-N - [[4- (3-methylbutyl) phenyl] methyl] -N '- (2,4,6-trifluorophenyl) -urea 40 µg 2 ~ ai3 °, 21 * CH3 e 3 50

DK 160869B

42 IC50 (MM) * 5 7.

N '- (4-Chloro-2,6-dimethylphenyl) -N-heptyl-NC [4- (3-methylbutyl) phenyl] methyl] -urea 10a-ί cHj-aiz-CH-aij 15 * -O / 13 20 * Concentration of compound to achieve 50% inhibition of ACAT enzyme activity.

25

It is clear from the results that the compounds of the invention exhibit superior ACAT enzyme inhibitory activity over the known compounds.

Claims (4)

1. Analogous Process for Preparing Substituted Urea or Thiourea Compounds of General Formula I Wherein X is at least one substituent selected from hydrogen, C 1-4 alkyl, hydroxy, C 1-4 alkoxy, phenoxy, amino, halogen, trihalomethyl, C 1-4 alkylamido and nitro, 15. is oxygen or sulfur, R 1 and R 2 are different and are each selected from C 4-12 alkyl, C 4-12 cycloalkylalkyl, C 7-14 phenylalkyl, and C 7-14 phenylalkyl, wherein the phenyl ring carries at least one substituent selected from C 1-10 alkyl, C 1-6 alkoxy, phenoxy , benzyloxy, methylenedioxy, C1-4 alkylthio, phenyl, halogen, trihalomethyl, adamantyl and nitro, R3 is selected from hydrogen, C1-4 alkyl, benzyl, benzyl with at least one substituent Z, naphthyl, phenyl and phenyl with at least one substituent Z, where Z is selected independently of X 25 from the meanings given for X, characterized in that a) a compound of the formula 30 Y II ACB wherein Y is as defined above and A and B are each selected from halogen, C 1-4 alkoxy, C 1-4 alkylthio, phenoxy, 4-chlorophenoxy or 4-nitrophenoxy, reacted with aryl amine of formula DK 160869B Η NH 5 wherein X and R3 have the meaning given above to give an intermediate of formula R3 '/ lf Ji-CB-0 and then the intermediate is reacted with a secondary amine of formula 15% / HN \ 20 R 2 wherein R 1 and R 2 are as defined above, or b) a compound of formula Y 25 || A-C-B wherein Y, A and B are as defined above are reacted with a secondary amine of the formula 30 Rx / HN \ R2 35 where R1 and R2 have the meaning given above to give an intermediate of the formula Y Ri 40 || ACN \ R2 DK 160869 B, whereupon the intermediate is reacted with an aryl amine of formula R3 λ NH 5 x - wherein X and R3 are as defined above, or c) an arylisocyanate or arylthioisocyanate of formula 10 is reacted with a secondary amine of formula 15 Ri 2, where X, Y, R 2 and R 2 have the meanings given above. Process according to claim 1, characterized in that 1- (n-heptyl) -1- [4- (2,2-dimethylpropyl) phenylmethyl] -3- (2,4-difluorophenyl) urea is prepared. Process according to claim 1, characterized in that 1- (n-heptyl) -1- [4- (2,2-dimethylpropyl) phenylmethyl] -3- (4-chloro-2,6- dimethyl-phenyl) -urea. Process according to claim 1, characterized in that 1- (n-heptyl) -1- [4- (2,2-dimethylpropyl) phenylmethyl] -3- (2,4,6- trifluorophenyl) -urea.