FI85013C - Process for preparing anti-arteriosclerotic substituted k arbamide derivatives - Google Patents

Description

1 85013

Method for preparing substituted urea derivatives for arteriosclerosis

The invention relates to a process for the preparation of therapeutically useful compounds of formula I.

HOR, \ "m 10 x-qDJ ^ r2 wherein X represents two or three substituents selected from C1-C4-alkyl and halogen; R1 is C4-C7-alkyl; and R2 is benzyl having a substituent on the phenyl ring. one C1-C6 alkyl group, and for the preparation of their salts.

The compounds of formula I are arteriosclerotic agents which can alleviate atherosclerosis by preventing the formation and development of atheromas in the walls of mammalian blood vessels.

A number of urea and thiourea compounds have been described in the literature, e.g. in J. Med. Chem. 18, 1024 (1975); Chem. Absts. 95: 6758m 25 (1981) and 91: 74631g (1979); U.S. Patent Nos. 2,668,039, 3,335,142, 3,856,952, 3,903,130 and DE Application Publication No. 2,928,485. The compounds described in the literature are reported to have use as herbicides, pesticides, fungicides, algicides, photosensitizers, anthelmintics, sympatholytics. and as antiviral agents. The compounds described in DE-A-2 928 485 are reported to be useful lipid absorption inhibitors. However, the literature does not describe substituted urea compounds of formula I or the use of such compounds for the treatment of atherosclerosis and hyperlipidemia.

2 85013

Arteriosclerosis is a form of arteriosclerosis characterized by the accumulation of lipids on the walls of both medium and large arteries and the thickening of the arterial walls. As a result, the walls of the blood vessels weaken, their elasticity decreases and their effective internal dimension decreases. Arteriosclerosis is the most common cause of cardiac anemia and is of great importance because occlusion of medium to large arteries reduces the blood supply to vital organs such as the heart muscle and brain. Causes of atherosclerosis include heart failure, heart damage, life-threatening arrhythmia, senility and paralysis. The fact that cholesterol is the main ingredient in atherosclerotic lesions, or plaques, has been known for over a hundred years. Several researchers have studied the role of cholesterol in the onset and development of damage and also, more importantly, how the onset and development of damage can be prevented or how damage can be repaired. Atheroma lesions have been shown to contain more esterified cholesterol than the surrounding non-diseased vascular wall containing more unesterified cholesterol [Adams et al. Atherosclerosis, 13, 429 (1974)].

The intracellular esterification of cholesterol with fatty acids is catalyzed by the enzyme fatty acyl-CoA: your cholesterol acyltransferase, or ACAT, and the accumulation and accumulation of cholesteryl esters in vascular walls is dependent on the increased activity of this enzyme [28], )]. In addition, cholesteryl esters are removed from cells at a lower rate than unesterified cholesterol [Bonjers and Bjorkerud, Atherosclerosis, 15, 273 (1972) and 22, 379 (1975)]. Thus, inhibition of the ACAT enzyme could lower the rate of cholesterol esterification, reduce the accumulation and accumulation of cholesteryl esters in vascular walls, and prevent or inhibit the formation and development of atheroma lesions. The compounds of the formula I are very potent inhibitors of the ACAT enzyme. These compounds are thus useful in controlling and lowering the concentration of cholesteryl-5 in the walls of mammalian blood vessels and in preventing the accumulation and accumulation of cholesterol in the walls of mammalian blood vessels. In addition, the compounds of formula I prevent the onset and development of atherosclerotic lesions in mammals.

10 The evidence that hyperlipidemia is one of the factors associated with coronary heart disease is very convincing. A very significant study in Framin-Ham, Massachsetts (Gordon and Verter, 1969), which studied more than 5,000 hen-15 pounds over 12 years, found a correlation between high blood cholesterol levels and heart attacks. Although there are several causes of coronary heart disease, one of the most obvious constant factors is elevated plasma lipid concentration. The combined elevated cholesterol and triglyceride levels have been shown to have the greatest potential for coronary artery disease (Carlson and Bottiger, 1972). Hyperlipoproteinemia with very low and / or low density lipoproteins was observed in the majority of patients with cardiac anemia or peripheral vascular disease (Lewis et al., 1974).

It has been shown that certain members of compounds in this class are able to reliably and effectively lower both serum ml-30 levels in warm-blooded animals. Such an effect on serum lipids is considered to be very valuable in the treatment of atherosclerosis. For some time, it has been considered desirable to lower serum lipid levels and correct lipoprotein balance in mammals as a prophylactic measure for atherosclerosis. The compounds of formula I do not act by inhibiting the late stages of cholesterol synthesis and thus do not cause the accumulation of intermediates such as desmosterol, the accumulation of which is as undesirable as the accumulation of cholesterol itself. The compounds of formula I, which have a combination of therapeutically advantageous properties, can be safely administered to warm-blooded mammals for the treatment of hyperlipidemic and atherosclerotic conditions in patients with a predisposition to, or having, a heart attack, peripheral or cerebrovascular accident or stroke. already is.

The process of the invention for the preparation of compounds of formula I is characterized in that a) an aryl isocyanate of formula 15 is reacted with a secondary amine of formula 25 wherein X, R 1 and R 2 are as defined above, or b) a compound of formula is a formula

30 O

tl

A-C-B

wherein A and B are independently halogen, C 1 -C 4 alkoxy, C 1 -C 4 alkylthio, phenoxy, 4-chlorophenoxy 35 or 4-nitrophenoxy, are reacted with an arylamine of formula 5 85013 5 wherein X is as defined above and the intermediate obtained from formula 10 H o

\ H

Θν-c-b 15 is reacted with a secondary amine of the formula HN <^ 20 ^ "^ R2 wherein Rx and R2 are as defined above, or c) a compound of the formula

25 O

II

A-C-B

wherein A and B are as defined above, are reacted with a secondary amine of formula 30 HNv.

35 wherein R 1 and R 2 are as defined above, and the resulting intermediate of formula 6 85013 0 A-C-N <^ 5 is reacted with an arylamine of formula

.NH

X - Cr 2 i 2 wherein X is as defined above, and if desired the compound thus obtained is converted into a salt.

The most preferred compounds of formula I are those in which X is at least one methyl or chloro substituent.

The novel compounds of formula 1 can be used to treat atherosclerosis, to reduce vascular wall cholesterol, to prevent the development of atherosclerotic lesions and / or to treat hyperlipidemia in mammals in need of such treatment.

Some of the ureas of formula I are prepared according to option c by reacting an activated derivative of a carboxylic acid, such as phosgene or phenyl chloroformate, with a secondary amine to give an intermediate, for example disubstituted carbamyl chloride. This intermediate is in turn reacted with an arylamine to form a urea. The preparation of the intermediate is carried out in an aprotic solvent such as tetrahydrofuran, toluene, xylene or the like at a temperature between room temperature and the boiling point of the solvent. The intermediate can be isolated by evaporation of the solvent and, if necessary, purified by distillation. The intermediate is then reacted with an arylamine 35 in an aprotic solvent such as dimethylacetamide in the presence of a base, e.g. sodium hydride, at a temperature from about room temperature to the boiling point of the solvent used. An example of this reaction is the reaction between phosgene and N-benzyl-n-butylamine in toluene described in Preparation 1 to give N-benzyl-N- (n-butyl) carbamyl chloride as intermediate 5, which is then reacted with diphenylamine, N, N- in dimethylacetamide in the presence of sodium hydride to give 1-benzyl-1- (n-butyl) -3,3-diphenylurea.

Other ureas of formula I are prepared according to process option b by reacting an arylamine and an activated carboxylic acid derivative such as phosgene to give an intermediate, for example aryl carbamyl chloride. This intermediate is then reacted with a secondary amine to give the urea. This intermediate is prepared in an aprotic solvent such as tetrahydrofuran, toluene or xylene at a temperature between about room temperature and 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, e.g. toluene, at a temperature from room temperature or below to the boiling point of the solvent. An example of this reaction is the reaction of phosgene and N-phenyl-3-chloroaniline described in Preparation 2 to give the intermediate N- (3-chlorophenyl) -N-phenylcarbamyl chloride, which is then reacted with N-benzyl-n-butylamine 1- benzyl-1- (n-butyl) -3- (3-chlorophenyl) -3-phenyl-urea.

Many of the ureas of formula I are prepared according to option a by reacting the aryl isocyanate with a secondary amine. Such a reaction can be carried out in an aprotic solvent such as hexane, diethyl ether, toluene, tetrahydrofuran or the like at a temperature from room temperature to 85013 or below to the boiling point of the solvent used. The ureas are isolated by filtration or evaporation of the solvent and can be purified by recrystallization, absorption chromatography or distillation under reduced pressure.

Several of the secondary amines required for the synthesis of ureas of formula I are prepared by reduction of the corresponding amides with diborane. An example of this reaction is the synthesis of N- (n-butyl-10R) -2-chlorobenzylamine described in Preparation 5 by reduction of N- (n-butyl) -2-chlorobenzamide with diborane. Certain amides required for these reductions are prepared by acylation of primary amines with carboxylic acids in a manner well known to those skilled in the art, for example by converting a carboxylic acid to the corresponding carboxylic acid chloride by reaction with thionyl chloride and reacting the acid chloride with a primary amine. Particularly preferably, this is done by reacting the carboxylic acid with a primary amine in the presence of boron trifluoride etherate as a catalyst. As an example of this reaction, the boron trifluoride etherate catalyzed acylation of 2-chlorobenzylamine with 3-methoxyphenylacetic acid to N- (2-chlorobenzyl) -3-methoxyphenylacetamide is described in Preparation 4.

The ureas of the formula I are obtained as crystalline solids or distillable liquids. They can be characterized by precise melting or boiling points and typical spectra. They are significantly soluble in organic solvents, but are usually less soluble in water.

The properties and utility of the compounds of formula I are set out in the specific tables below.

The compounds of formula I were analyzed by determining their biological activity in two experiments demonstrating their use as antiatherosclerotic agents. The ability of the compounds to inhibit enzyme fat acyl-Co-cholesterol acyltransferase (ACAT) was determined in vitro, and their serum hypolipidemic activity was determined by measuring their ability to inhibit lipid absorption in rats. The ability of the compounds to inhibit ACAT was determined as follows: Rat adrenal glands were homogenized in 0.2 M KH 2 PO 4 buffer (pH 7.4), and the homogenate was centrifuged at 1000 G for 15 minutes at 5 ° C. The supernatant containing 10 microsomal fractions was used as a source of cholesterol esterifying enzyme, fatty acyl-CoA: cholesterol acyltransferase (ACAT). A mixture of 50 parts adrenal supernatant, 10 parts albumin (BSA) (50 mg / ml), 3 parts test compound (final concentration 5.2 pg / ml) and 500 parts buffer was preincubated at 37 ° C for 10 hours. minutes.

To the mixture was added 20 parts of oleoyl-CoA (14C-0.4 Ci), and the mixture was incubated at 37 ° C for 10 minutes. A control mixture without test compound was prepared in the same manner. The lipids of the incubated mixture were extracted into organic solvent 20 and separated by thin layer chromatography. The cholesteryl ester fraction was determined on a liquid scintillation counter. This method is a modification of the method described by Hashimoto et al., Life Science, 12 (Part II), 1-12 (1973).

The results obtained in this experiment with representative compounds of formula I are shown in Table I.

10 8501 3

Table I

Compound Inhibition% 3- (2,4-Difluorophenyl) -1 - ([4- (2,2-5 dimethylpropyl) phenyl] methyl} -1-beptylurea 95 3- (4-chloro-2,6-dimethylphenyl) 1 - {[4- (2,2-dimethylpropyl) phenyl] methyl} -1-heptyl-10-urea 95 1 - {[4-2,2-dimethylpropyl) phenyl] methyl} -1-heptyl-3 - ( 2,4,6-Trifluorophenyl) urea 95 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 20 1- (n-butyl) -1- (4-tert-butylbenzyl) -3- (2,4 -dimethylphenyl) urea 96.4 1- (n-butyl) -1- [4- (n-hexyl) benzyl] -3-25 (2,4-dimethylphenyl) urea 93.8 1- (n-heptyl) - 1- (4-n-butylbenzyl) -3- (2,4-dimethylphenyl) urea 94.8 30- (n-heptyl) -1- (4-n-butylbenzyl) -3- (2,4,5 -trimethylphenyl) urea 95.3 1- (n-heptyl) -1- (4-n-butylbenzyl) -3- (2,4-dichlorophenyl) urea 80.0 35 11 8501 3

Table I

Compound Inhibition% 1- (n-heptyl) -1- (4-n-butylbenzyl) -3-5 (2,4,6-trichlorophenyl) urea 90.0 1- (n-heptyl) -1- (4 -n-butylbenzyl) -3- (2,4,5-trichlorophenyl) urea 46.5 10 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 15

Inhibition of cholesterol absorption was determined by feeding male Sprague-Dawley rats (weight 150-170 g) for 2 weeks with 1% cholesterol: 0.5% cholic acid. The diet also contained 0.03% of the compounds tested. Control rats received the same diet without test compound. At the end of the experiment, the rats were killed by cutting the neck. Blood was collected and centrifuged at 1500 g for 10 minutes at 4 ° C. The obtained serum was enzymatically analyzed for cholesterol and triglycerides by the method of 25 P. Trinder. Analyst, 77, 321 (1952), using a Centrifichem 400 Analyzer. The livers of the rats were separated and a 0.4 g sample was taken from the center of their large block and saponified in 25% KOH ethanol solution. The obtained neutral sterols were extracted with petroleum ether and the cholesterol was analyzed from the extract. The effect of the compound on the inhibition of cholesterol absorption is obtained from the reduction of either serum cholesterol or liver cholesterol compared to the corresponding values in the control group of rats.

The results obtained in this experiment with the usual compounds of formula I are summarized in Table II.

i2 8 5 01 3

Active compounds are those that statistically significantly inhibit cholesterol absorption. Liver sterol value (LS) and serum sterol value (SS) are expressed as a percentage of the reference value.

5 Table II

Compound_LS SS

3- (2,4-Difluorophenyl) -1 - {[4- (2,2-dimethylpropyl) phenyl] methyl} -1-heptylurea 3- (4-chloro-2,6-dimethylphenyl) - 1 - ([4- (2,2-dimethylpropyl) phenyl] methyl} -1-heptylurea 17 31 15 1 - {[4- (2,2-dimethylpropyl) phenyl] methyl} -1-heptyl-3- (2,4,6-trifluorophenyl) urea 14 21 1- (n-heptyl) -1- (4-n-butylbenzyl) -20 3- (2,4-dimethylphenyl) urea active 1- (n-heptyl) -1- (4-n-butylbenzyl) -3- (2,4,5-trimethylphenyl) urea active 1- (n-heptyl) -1- (4-n-butylbenzyl) -3- (2,4- dichlorophenyl) urea active 1- (n-heptyl) -1- (4-n-butylbenzyl) -3- (2,4,6-trichlorophenyl) urea active 1- (n-heptyl) -1- (4-n -butylbenzyl) -3- (2-methyl-4-chlorophenyl) urea active 1- (n-heptyl) -1- (4-n-butylbenzyl) -35 3- (2,4-difluorophenyl) urea active i3 8501 3

The experiments in Tables I-II have actually been performed and the results presented in them have been achieved or derived from the results obtained.

When used for the above purposes, the compounds may be mixed with one or more pharmaceutically acceptable carriers, such as a solvent, diluent or the like, and administered orally, for example, as tablets, capsules, dispersible powders, granules, suspensions, containing, for example, about 0.5-5% of a suspending agent, as syrups containing e.g. about 10-50% sugar, or as elixirs containing e.g. about 20-50% ethanol; or they may be administered in parenteral dosage forms as sterile injectable solutions or suspensions containing about 0.5-5% of a suspending agent in an isotonic medium. These pharmaceutical preparations may contain, for example, from about 0.5 to about 90% of active ingredient together with a carrier, usually from 5 to 60% by weight.

The amount of antiatherosclerotic active agent used may vary depending on the particular compound used and the mode of administration and the condition of the patient being treated. However, in general, satisfactory results are obtained when the compounds of the formula I are administered in daily doses of about 2 to 500 mg / kg of body weight, which dose is preferably administered in 2 to 4 divided doses per day or in the form of a sustained-release preparation. In most large mammals, the daily dose is about 100-5000 mg, preferably about 100-2000 mg. Oral dosage forms contain from about 25 to about 500 mg of active ingredient in good admixture with a solid or liquid pharmaceutically acceptable carrier. This dosage regimen can be adjusted to obtain the optimal therapeutic response. For example, the drug 35 may be administered in multiple doses per day or the dose may be reduced depending on the therapeutic situation. In practice, it is highly preferred that these i4 8501 3 active compounds can be administered orally as well as intravenously, intramuscularly or subcutaneously as needed. Solid carriers include, for example, starch, lactose, dicalcium phosphate, microcrystalline cellulose, sucrose and kaolin, and liquid carriers include, for example, sterile water, polyethylene glycols, nonionic surfactants and vegetable oils such as corn, peanut and peanut oil. , the carrier being selected according to the active ingredient and the dosage form. Suitable excipients are the pharmaceutically commonly used excipients, e.g. flavors, colors, preservatives and antioxidants, for example vitamin E, ascorbic acid, BHT and BHA.

Pharmaceutical compositions which are preferred for the manufacture and administration of the drug include solid compositions, especially tablets and capsules filled with a solid or liquid. The most preferred route of administration is oral.

The active compounds can also be administered parenterally or intraperitoneally. The active compounds as free bases or pharmacologically acceptable salts can be prepared as solutions or suspensions in water, which preferably also contains a surfactant, e.g. hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof with oils. Under normal conditions of storage and use, these preparations contain a preservative to prevent the growth of micro-organisms.

Pharmaceutical compositions suitable for injection include aqueous solutions or dispersions or sterile powders for the extemporaneous preparation of a sterile injectable solution or dispersion. In all cases, the preparation must be sterile and must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must contain a preservative against the action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g.

glycerol, propylene glycol or liquid polyethylene glycol), suitable mixtures thereof or vegetable oils.

The preparation of representative compounds of formula I is described in the following preparations and examples:

Preparation 1 1-Benzyl-1- (n-butyl) -3,3-diphenylurea A solution of 20.0 g of phosgene and 100 ml of toluene is stirred at 0 ° C while N-benzylate is added to the solution over 15 minutes. A solution of n-butylamine (32.6 g) in 50 ml of toluene. The mixture is filtered and the filtrate is evaporated. The residue is distilled at 105 ° C under reduced pressure (250-350 μm) to give N-benzyl-N- (n-butyl) carbamoyl chloride as a colorless liquid.

A solution of diphenylamine (3.89 g) in 25 ml of dimethylacetamide is added with stirring over 1 hour at 45-50 ° C under nitrogen under N-benzyl-N- (n-butyl) carbamyl chloride (5.19 g), sodium hydride (0.685 g) and dimethylacetamide (65 ml). The mixture is stirred for 2 hours at 50 ° C, then the mixture is poured into water. The mixture is extracted with methylene chloride and the extract is evaporated. The residue is purified by chromatography on silica gel using an absorbent and eluting with an acetone-hexane mixture. The residue obtained after evaporation of the eluate is distilled at 165 ° C under reduced pressure (150 μm) to give 1-benzyl-1- (n-butyl) -3,3-diphenylurea as a viscous, clear, colorless liquid.

ie 6 5 01 3

Preparation 2 A solution of 1-benzyl-1- (n-butyl) -3- (3-chlorophenyl) -3-phenylurea-N-phenyl-3-chloroaniline (5.09 g) in 5 ml of toluene is added to phosgene. (4.70 g) and N, N-dimethylaniline (3.64 g) in toluene, the mixture is heated at 40 ° C and then stirred at room temperature for 45 minutes. The mixture is extracted with water, the organic layer is separated and evaporated to about half volume. To this solution is added 100 ml of toluene and then 9.80 g of N-benzyl-n-butylamine. The resulting mixture was stirred under reflux for 30 minutes, then washed with water, 1N hydrochloric acid and saturated sodium bicarbonate solution. The organic layer is separated, dried over sodium sulfate, treated with decolorizing carbon and evaporated. The residue is distilled at 185-189 ° C under reduced pressure (105 μm) to give 1-benzyl-1- (n-butyl) -3- (3-chlorophenyl) -3-phenylurea as a viscous, pale yellow liquid. .

Preparation 3 1-Benzyl-1- (n-butyl) -3- (2,4-dimethylphenyl) urea A solution of 2,4-dimethylphenyl isocyanate (4.89 g) in 100 ml of hexane is added to N-benzyl. To a solution of -n-butylamine (4.41 g) in 150 ml of hexane, and the solution is stirred at room temperature for 2 hours. The solution is evaporated and the residue is crystallized from pentane to give 1-benzyl-1- (n-butyl) -3- (2,4-dimethylphenyl) urea-30 dia, m.p. 70-71 ° C.

Preparation 4 N- (2-chlorobenzyl) -3-methoxyphenylacetamide 3-methoxyphenylacetic acid (12.5 g), 2-chlorobenzylamine (21.2 g), triethylamine (15.1 g), boron-35 trifluoride etherate (19, 3 ml) and a mixture of toluene (500 ml) i7 8501 3 are stirred and refluxed for 18 hours using a Dean-Stark water separator. The mixture is then allowed to cool and extracted with aqueous NaOH, dilute hydrochloric acid and water. The organic phase is evaporated and the residue is crystallized from hexane to give N- (2-chlorobenzyl) -3-methoxyphenylacetamide as a yellow solid, m.p. 89-91 ° C.

Preparation 5 N- (n-butyl) -2-chlorobenzylamine A cooled solution of N- (n-butyl) -2-chlorobenzamide (21.2 g) in 100 ml of tetrahydrofuran is added to 200 ml of a 1-m borane tetrahydrol solution. The mixture is stirred and refluxed for 18 hours, allowed to cool and treated with 6N hydrochloric acid. The organic solvent is evaporated and the residue is taken up in ether and aqueous NaOH. The ether layer is separated, dried and evaporated. The residue is distilled to give N- (n-butyl) -2-chlorobenzylamine as a colorless liquid, b.p. 65-75 ° C.

20 Examples 1-15

The compounds summarized in Table III were prepared from the appropriate aryl isocyanates and secondary amines by the method described in Preparation 3.

Table III

25 Eg Compound_Sp.

11- (n-butyl) -1- (4-n-butylbenzyl) -3- (2,4-dimethylphenyl)

urea 60-62 ° C

2 1- (n-butyl) -1- (4-methylbenzyl) -3- (2,4-dimethylphenyl) urea oil 3 1- (n-butyl) -1- (4-tert-butylbenzyl) ) -3- (2,4-dimethylphenyl) -

urea 28-31 ° C

4 1- (n-butyl) -1- [4- (n-pentyl) -

35 benzyl] -3- (2,4-dimethylphenyl) urea 65-67 ° C

18 8501 3

Table III

For example, Compound_sp.

5 1- (n-butyl) -1- [4- (n-hexyl) benzyl] -3- (2,4-dimethylphenyl) -5 urea oil 6 1- (n-heptyl) -1- (4 -n-butylbenzyl) -3- (2,4-dimethylphenyl) yellow urea oil 7 1- (n-heptyl) -1- (4-n-butylbenzyl) -3- (2,4,5 -trimethylphenyl) yellow urea oil 8 1- (n-heptyl) -1- (4-n-butylbenzyl) -3- (2,4-dichlorophenyl) urea rubber 15 9 1- (n-heptyl) - 1- (4-n-Butylbenzyl) -3- (2,4,6-trichlorophenyl) urea rubber 1- (n-heptyl) -1- (4-n-butylbenzyl) -3- ( 2,4,5-Trichloro-phenyl) -urea rubber 11 1- (n-Heptyl) -1- (4-n-butyl-benzyl) -3- (2-methyl-4-chloro-phenyl) -urea Oil 12 1- (n-Heptyl) -1- (4-n-butylbenzyl-3- (2,4-difluorophenyl) urea oil 13 1- (n-heptyl) -1 - [[4- (2,2 -dimethylpropyl) phenyl] methyl] -3- (2,4-colorless difluorophenyl) urea oil 14 1- (n-heptyl) -1 - [[4- (2,2-dimethylpropyl) phenyl] methyl ] -3- (4-chloro-2,6-dimethylphenyl) -

urea 111-113 ° C

1- (n-heptyl) -1 - [[4- (2,2-dimethylpropyl) phenyl] methyl] -3- (2,4,6-colorless trifluorophenyl) urea oil 19501 3

Example 16 N '- (2,4-Difluorophenyl) -N-heptyl-N - {[4- (3-methylbutyl) phenyl] methyl} urea A solution of 0.78 g of 2,4-difluorophenyl iso -5 cyanate in 10 ml of hexane is added to a solution of 1.38 g of N-heptyl-4- (3-methylbutyl) phenylmethylamine in 5 ml of hexane. The solution thus obtained is stirred overnight at room temperature and then evaporated to dryness to give an oil. This oil is distilled to give 2.0 g of a colorless oil (150-160 ° C) as the main fraction. This oil is purified by flash chromatography using 5% ethyl acetate in hexam to give 1.87 g of the title product as a colorless oil.

Analysis for C26H36N2F2O Calculated: C, 72.53; H 8.43; N 6.51; F 8.82 Found: C 72.69; H 8.88; N 6.48; F 9.01

Example 17 N '- (4-chloro-2,6-dimethylphenyl) -N-heptyl-N - {[4- (3-methylbutyl) phenyl] methyl] urea To a solution of 1.38 g of N-heptyl-4- (3-methyl-butyl) phenylmethylamine in 10 ml of dichloromethane, a filtered solution of 0.91 g of 4-chloro-2,6-dimethylphenyl isocyanate in 20 ml of dichloromethane is added. The resulting solution was stirred at room temperature overnight and then evaporated to dryness to give a pale yellow oil. This oil is flash chromatographed using ethyl acetate: hexane (0.5: 9.5). Fractions 6-22 are combined, evaporated to a pale yellow oil and flash chromatographed using ethyl acetate: hexane (0.5: 9.5). Fractions 12-20 are combined and evaporated to give 600 mg of the title product as an oil.

Analysis for C28H41N2C10

Calculated: C 73.57; H 9.04; N 6.13; Cl 7.76 35 Found: C 73.75; H 9.15; N 6.01; Cl 7.58.

2o 8501 3

Example 18 3- (4-Chloro-2,6-dimethyl-phenyl) -1 - {[4- (2,2-dimethyl-propyl) -phenyl] -methyl} -1-heptyl-urea To a cold solution of 2.47 g (0 , 0163 mol) of 4-5 chloro-2,6-dimethylphenylamine and 2.4 ml (0.0189 mol) of N, N-dimethylaniline in 80 ml of toluene were added dropwise a solution of 2.56 g (0 .0163 mol) of phenyl chloroformate in 20 ml of toluene. The resulting mixture was stirred at room temperature for 90 minutes and then diluted with water. The resulting two layers were separated. The organic layer was washed with two 40 mL portions of 3M hydrochloric acid followed by saturated brine. The organic solution was dried over anhydrous magnesium sulfate and filtered. The filtrate was evaporated in vacuo to give a white solid. The solid was recrystallized from a mixture of ethyl acetate and hexane to give 3.8 g of (4-chloro-2,6-dimethyl-phenyl) -carbamic acid phenyl ester as a white solid, m.p. 158-160 ° C.

A mixture of 1.11 g (0.004 mol) of (4-chloro-2,6-dimethyl-phenyl) -carbamic acid phenyl ester, 1.10 g (0.004 mol) of 4- (2,2-dimethyl-propyl) -N-heptyl-phenylmethyl-amine and The mixture was cooled, washed with two 30 ml portions of 1 M sodium hydroxide and then saturated brine, dried over anhydrous magnesium sulfate and filtered, and the filtrate was evaporated in vacuo to give an oil. 145-155 ° C / 0.1 mmHg) gave 1.47 g of a colorless oil which solidified on standing to give the title product as a white solid, mp 111-113 ° C.

Example 19 3- (2,4,6-Trifluorophenyl) -1 - {[4- (2,2-dimethylpropyl) phenyl] methyl) -1-heptylurea To a cold solution of 5.3 g (0.0359 mol) ) 2,4,6-trifluoroaniline and 5.6 ml (5.4 g; 0.044 mol) of N, N-2 8501 3 dimethylaniline in 70 ml of toluene were added dropwise a solution of 5.63 g (0 .0359 mol) of phenyl chloroformate in 20 ml of toluene. The resulting mixture was stirred at room temperature for 16 hours during which time 5 precipitate formed. The mixture was diluted with ethyl acetate and water to separate the two layers. The organic layer was washed with two 50 mL portions of 3M hydrochloric acid followed by two 50 mL portions of saturated brine. The solution was dried over anhydrous magnesium sulfate and filtered. The filtrate was evaporated in vacuo to give a white solid. The solid was triturated with hexane, collected by filtration, washed with hexane and dried to give 8.38 g (96% yield) of (2,4,6-trifluorophenyl) -carbamic acid phenyl ester as a white solid, m.p. 127-128 ° C.

A mixture of 0.97 g (0.004 mol) of (2,4,6-trifluorophenyl) carbamic acid phenyl ester, 1.10 g (0.004 mol) of 4- (2,2-dimethylpropyl) -N-heptylphenylmethylamine and 40 ml of toluene, heated at reflux for two hours. The mixture was cooled, washed with two 30 mL portions of 1 M sodium hydroxide and then brine. The solution was dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to give a pale yellow oil. Distillation (140-150 ° C / 0.08 mmHg) gave 1.5 g of a colorless oil. A 900 mg portion of this oil was redistilled (140-150 ° C / 0.160 mmHg) to give 500 mg of the title product as a colorless oil.

Example 20 N-Heptyl-N - {[4- (3-methylbutyl) phenyl] methyl] -N1- (2,4,6-trifluorophenyl) urea A solution of 1.10 g of N-heptyl-4- ( 3-methyl-butyl) phenylmethylamine, 1.07 g of N- (2,4,6-trifluoro-35-phenyl) phenylcarbamate and 30 ml of toluene, are heated under reflux for 1.5 hours and then cooled. . The mixture is washed with 1.0 N sodium hydroxide and water, dried, filtered and evaporated to give a pale yellow oil. This oil is purified by flash chromatography using ethyl acetate: hexane (0.5: 9.5). The pure fractions were combined and evaporated to give 1.5 g of the title product as a colorless oil.

Analysis for C26H35F3O Calculated: C, 69.62; H 7.86; N 6.25; F 12.71 Found: C 70.03; H 7.85; N 6.23; F 12.93

Claims (5)

A process for the preparation of therapeutically useful compounds of the formula I 5 H 0 R, \ 1 ^ / "\, Nc-rr (I) x-Cf) 1 \ 10 r2 wherein X represents two or three substituents from the following : C 1 -C 4 alkyl and halogen, R x is C 4 -C 7 alkyl, and R 2 is benzyl having one C 1 -C 6 alkyl group as a substituent on the phenyl ring, and for the preparation of their salts, characterized in that a) an aryl isocyanate, is reacted with a secondary amine of the formula HN <^ 30 ^ ^ R2 wherein X, Rj and R2 are as defined above, or b) a compound of the formula O Α- <ϋ-Β 2 «8 501 3 wherein A and B are independently halogen, C 1 -C 4 alkoxy, C 1 -C 4 alkylthio, phenoxy, 4-chlorophenoxy or 4-n.-nitrophenoxy groups, is reacted with an arylamine of formula 5 '- X wherein X is as defined above and the resulting intermediate of formula H 1 (- \ "* - {oJ is reacted with a secondary amine of formula ^ R1 HN ^ 25 wherein R2 and R2 are as defined above, or c) a compound of formula 0 II ACB 30 wherein A and B are the same as above is reacted with a secondary amine of formula 35 HN ^ 25 8 5 01 3 wherein R 1 and R 2 are as defined above and the intermediate obtained from the formula O 2 R, II A-C-N <T R2 is reacted with an arylamine of formula Where X is the same as above, and if desired, the compound thus obtained is converted into a salt. 26 8 501 3 Förfarande förställning av therapeutiskt an-vändbara föreningar Raed formuleln I 5 H \? / R1 Xr2 10 2 to X is a substituent or a substituent having the following substituents: C1-C4-alkyl and halogen; R 1 is C 4 -C 7 alkyl; and R 2 is ben-15 syl, wherein the phenyl ring is substituted with a C 1 -C 6 alkyl group; and in the case of a compound having a color of 20 - £ sr 25 in the form of a secondary amine having a color of X, Rx and R2 of the same formula as in the case of b, or b) in the case of formula 35 0 II ACB 27 8 5 01 3 for the addition of halogen, C 1 -C 4 alkoxy, C 1 -C 4 alkylthio, phenoxy, 4-chlorophenoxy or 4-nitrophenoxy groups, optionally with arylamine, in the form of 5 * - € r 10 to X in the form of one or more of the same products as in the form \ n 15 in the case of the second Amine, in the form of 20 hnC ^ r2 of the Rx and R2 of the same as 25 c) in the case of formula 0 ll ACB 30 from A and B in the same case as above, in the case of the second Amine in the form of ^ ^ "Rl HNCT 35 28 ti 5 01 ό där Rx och R2 betecknar samma som ovan, och den obtained from the products of Formula II 5 A-C-N <T omsätts med en arylamin, som har formeln 10 NH x ^ r2 15 där X betecknar samma som ovan, och if ali önskvärt.