NO158417B - ANALOGUE PROCEDURE FOR THE PREPARATION OF PHARMACOLOGICALLY ACTIVE URINENTS AND TIOUR INGREDIENTS. - Google Patents

Description

The present invention relates to the production of new substituted urea and thiourea compounds which can be used as pharmaceuticals. Connect-

The agents produced according to the invention are antiatherosclerotic agents that can alleviate atherosclerosis by counteracting the formation or development of atheromatous lesions in the blood vessel walls of mammals. Pharmaceutical preparations containing the compounds prepared according to the invention can be used in the treatment of diseases in mammals. In the treatment of atherosclerosis, the course of the disease can be prevented, stopped or reversed.

A number of urea and thiourea compounds are described in the literature, for example in J. Med. Chem. 18, 1024

(1975); Chem. Abs. 95: 6758m (1981) and 91: 74631g (1979);

US Patent No. 2,688,039; 3,335,142; 3,856,952; 3,903,130 as well as in German publication no. 29 28 485. The compounds indicated in the literature are described as useful herbicides, plant growth regulators, bactericides, pesticides, fungicides, algicides, photographic sensitizers, anthelmintic, sympatholytic and antiviral agents. The urea compounds indicated in Publication No. 29 28 485 are described as useful for inhibiting lipid absorption. However, there are no literature references that describe the tetra-substituted urea and thiourea compounds produced according to the present invention, or their use in the treatment of atherosclerosis or hyperlipidemia.

Atherosclerosis is a form of arteriosclerosis characterized by lipid accumulation in and thickening of the blood vessel walls in both medium-sized and large arteries. The blood vessel walls are thereby weakened, and the elasticity and effective internal size of the arteries is reduced. Atherosclerosis is the most common cause of ischemic heart disease and is of great medical importance, since the blockage of medium and large arteries reduces the blood supply to vital organs such as the heart valves and the brain. Diseases that occur as a result of atherosclerosis include ischemic heart disease, heart failure, life-threatening arrhythmia, senility and stroke.

The fact that cholesterol is a major component of atherosclerotic lesions or plaques has been known for more than a hundred years. Various researchers have studied the role of cholesterol in lesion formation and development and also, which is more significant, whether lesion formation can be prevented or lesion development halted or reversed. Atheromatous lesions have now been shown [Adams, et al., Atherosclerosis, 13, 429 (1974)] to contain a greater amount of esterified as opposed to unesterified cholesterol than the surrounding non-diseased blood vessel wall. The 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 cholesteryl esters in the blood vessel wall is associated with increased activity of this enzyme [Hashimoto and Dayton, Atherosclerosis, 2_8, 447 (1977)] . Moreover, cholesteryl esters are removed from the cells at a lower rate than unesterified cholesterol [Bondjers and Bjorkerud, Atherosclerosis, 1_5, 273 (1972) and 22, 379 (1975)]. Thus, inhibition of the ACAT enzyme should lower the rate of cholesterol esterification, reduce the accumulation and storage of cholesteryl esters in the blood vessel wall and prevent or inhibit the formation and development of atheromatous lesions. The compounds produced according to the invention are very potent inhibitors of the ACAT enzyme. Consequently, these compounds are useful for controlling and reducing the cholesteryl ester content in the blood vessel walls of mammals as well as for reducing the accumulation and storage of cholesterol in the blood vessel walls of the mammals. Furthermore, the compounds produced according to the invention inhibit the formation or development of atherosclerotic lesions in mammals.

The evidence that hyperlipidemia is one of the factors involved in coronary heart disease is very impressive. A very important study conducted in Framingham, Massachusetts (Gordon and Verter, 1969) involving more than 5,000 people over a longer period of time than 12 years established a relationship between high concentrations of blood cholesterol and an increased risk of heart attack. Although the causes of coronary artery disease are several, one of the most constant factors has been the elevated concentration of lipids in the blood plasma. A combined increase in cholesterol and triglycerides has been shown (Carlson and Bottiger, 1972) to entail the greatest risk of coronary heart disease. The majority of patients with ischemic heart disease or peripheral vascular disease have been found to suffer from hyperlipoproteinemia which included very low density and/or low density lipoproteins (Lewis, et al., 1974).

It has now been found that certain members of this class of compounds can lower both serum lipids in warm-blooded animals.

Such an effect on serum lipids is considered very valuable in the treatment of atherosclerosis. It has for some time been considered desirable to lower the serum lipid contents and correct the lipoprotein balance in mammals as a preventive measure against atherosclerosis. The compounds produced according to the invention do not act by blocking late stages of cholesterol biosynthesis and consequently do not lead to the accumulation of intermediate products such as desmosterol, which is as undesirable as cholesterol itself. Compounds with the combination of therapeutically beneficial properties exhibited by the compounds prepared according to the invention can be safely administered to warm-blooded mammals for the treatment of hyperlipidemic and atherosclerotic conditions found in patients with or prone to myocardial infarction, peripheral or cerebral vascular disease and stroke.

The compounds produced according to the invention exhibit antiatherosclerotic activity, and the invention shall not be bound to any particular mechanism for antiatherosclerotic action.

According to the present invention, certain new compounds are produced which can be represented by formula I:

where X denotes at least one substituent selected from hydrogen, Ci-C4 alkyl, hydroxy, Ci-C4 alkoxy, phenoxy, amino, halogen, trihalomethyl, Ci-C4 alkylamido and nitro,

Y is selected from oxygen and sulfur,

R 1 and R 2 are different and are independently selected from C 4 -C 1 2 alkyl, C 4 -C 1 2 cycloalkylalkyl, C 7 -C 1 -1 phenylalkyl and

C7-C14 phenylalkyl where the phenyl ring has at least one substituent selected from C1-C10 alkyl, C1-C10 alkoxy, phenoxy, benzyloxy, methylenedioxy, C1-C4 alkylthio, phenyl, halogen, trihalomethyl, adamantyl and nitro;

R3 is chosen from hydrogen, C1-C6 alkyl, benzyl, benzyl with at least one substituent Z, naphthyl, phenyl and phenyl containing at least one substituent Z, where Z independently of X is chosen from the meanings given for X.

Preferred compounds are those where Y is oxygen. More preferred are those where X represents at least one C 1 -C 4 alkyl or halogen substituent, and R 1 and R 2 are different and independently selected from C 4 -C 1 2 alkyl, C 7 -C 1 4 aralkyl and substituted C 7 - C 1 4 -aralkyl. Most preferred are those where X denotes at least one methyl or chlorine substituent, and Z is hydrogen, methyl or chlorine.

Particularly preferred compounds produced according to 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-(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]-3-(2,4,6-trifluorophenyl)urea .

According to the invention, the new compounds are produced by

a) an arylisocyanate or arylthioisocyanate of the formula:

is reacted with a secondary amine of the formula: where X, Y, R 1 and R 2 have the meanings given above, or b) a compound of the formula: where Y has the meaning given above, and A and B are independently selected from among halogen, C1-C6 alkoxy, C1-C4 alkylthio, phenoxy, 4-chlorophenoxy and 4-nitrophenoxy, is reacted with an arylamine of the formula: where X and R 3 have the meaning given above, to an intermediate with the formula after which the intermediate is reacted with a secondary amine of the formula where R 1 and R 2 have the above meaning, or c) a compound with the formula: where Y has the above meaning, and A and B are independently selected from halogen, Ci-C4 alkoxy, Ci-C4 alkylthio, phenoxy, 4-chlorophenoxy and 4-nitrophenoxy, is reacted with a secondary amine of the formula: where R 1 and R 2 have the meaning given above, to an intermediate with the formula: after which the intermediate is reacted with an arylamine of the formula:

where X and R3 have the meanings given above.

For the treatment of atherosclerosis, reducing the cholesterol content of the blood vessel wall, inhibiting the development of atherosclerotic lesions and/or treating hyperlipidemia in mammals in need of such treatment, an effective amount of a compound of the formula I set forth above is administered to the mammal.

A pharmaceutical preparation which is suitable for the treatment of atherosclerosis, to reduce the cholesterol content in the blood vessel walls, inhibit the development of atherosclerotic lesions and/or treat hyperlipidemia in mammals in need of such treatment, can be prepared by an effective amount of a compound with the Formula I above is mixed with a non-toxic, pharmaceutically acceptable carrier.

Certain of the ureas and thioureas listed above are prepared by reacting activated carboxylic acid derivatives, such as phosgene, thiophosgene or phenylchloroformate, with secondary amines to form an intermediate, for example a disubstituted carbamyl chloride. This intermediate is in turn allowed to react with an arylamine to form the urea or thiourea. The preparation of the intermediate product is carried out in an aprotic solvent such as tetrahydrofuran, toluene, xylene or the like, at temperatures from approximately room temperature up to the boiling point of the solvent. The intermediate product can be isolated by evaporation and purified by distillation if this is necessary. The intermediate is then allowed to react with an arylamine in an aprotic solvent such as dimethylacetamide, in the presence of a base, such as sodium hydride, at temperatures from about room temperature up to the boiling point of the solvent used. An example of this procedure is the reaction between phosgene and N-benzyl-n-butylamine in toluene to form the intermediate N-benzyl-N-(n-butyl)carbamyl chloride, which is then allowed to react with diphenylamine in N,N-dimethylacetamide in the presence of sodium hydride to form 1-benzyl-1-(n-butyl)-3,3-diphenylurea.

Other ureas and thioureas described above are prepared by reaction of arylamines with activated derivatives of carboxylic acid such as phosgene or thiophosgene to form an intermediate, for example an arylcarbamyl chloride. This intermediate is then allowed to react with a secondary amine to form the urea or thiourea. The production of this intermediate is carried out in an aprotic solvent such as tetrahydrofuran, toluene or xylene, at temperatures from approx. room temperature up to the boiling point of the solvent in the presence of a base, for example N,N-dimethylaniline. The intermediate is then allowed to react with a secondary amine in an aprotic solvent, e.g. toluene, at temperatures from room temperature or lower up to the boiling point of the solvent. An example of this process is the reaction between phosgene and N-phenyl-3-chloroaniline to form the intermediate N-(3-chlorophenyl)-N-phenylcarbamyl chloride, which is then reacted with N-benzyl-n-butylamine to form 1- benzyl-1-(n-butyl)-3-(3-chlorophenyl)-3-phenylurea.

The ureas and thioureas of formula I which contain carboxy groups are prepared by alkaline hydrolysis of corresponding carboalkoxyureas and -thioureas, prepared by the syntheses described above. In a similar way, the compounds containing hydroxy, mercapto or amino groups can be prepared by alkaline hydrolysis of corresponding O-acetyl, S-acetyl and N-acetyl ureas or -thioureas, the latter also being obtained by the urea and thio-urea syntheses described above. Alternatively, ureas and thioureas containing hydroxy groups can be prepared by cleavage of corresponding methoxy compounds using Lewis acids, e.g. bortribrdmid.

Certain substituted N-benzylanilines, which constitute intermediates necessary for the synthesis of some of the new tetra-substituted ureas and thioureas of formula I, are not known in the art. The necessary N-benzylanilines are prepared by reaction between various benzaldehydes and anilines to form anils. The anilines are then reduced to form the substituted N-benzylanilines. An example of such a synthesis involves the reaction between 2,4-dimethylbenzaldehyde and 2,4-dichloroaniline to form N-(2,4-dimethylbenzylidene)-2,4-dichloroaniline, followed by reduction with sodium borohydride to form N-( 2,4-dimethylbenzyl)-2,4-dichloroaniline.

Many of the carbamides and thiocarbamides of formula I are prepared by reaction of aryl isocyanates and aryl isothiocyanates with secondary amines. These reactions can be carried out in aprotic solvents such as hexane, diethyl ether, toluene, tetrahydrofuran and the like at temperatures from room temperature or lower 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 method is the reaction between 2,4-dimethylphenylisocyanate and di-(n-butyl)amine to form 1,1-di-(n-butyl)-3-(2,4-dimethylphenyl)urea.

Many of the secondary amines required for synthesis

of the ureas and thioureas of formula I, are prepared by diborane reductions of the corresponding amides. An example of

this reaction constitutes the synthesis of N-(n-butyl)-2-chlorobenzylamine with diborane reduction of N-(n-butyl)-2-chlorobenzamide. Certain of the amides that are necessary for these reductions are prepared by acylation of primary amines with carboxylic acids by methods known per se, for example by converting the carboxylic acid to the corresponding carboxylic acid chloride using thionyl chloride and reacting the acid chloride with the primary amine in presence of a base. A method that is particularly valuable for this conversion is the boron trifluoride ether-catalyzed reaction of a carboxylic acid with a primary amine. An example

on this conversion is the boron trifluoride ether-catalyzed acylation of 2-chlorobenzylamine with 3-methoxyphenylacetic acid to

to form N-(2-chlorobenzyl)-3-methoxy-phenylacetamide.

The ureas and thioureas of formula I are obtained as crystalline solids or distillable liquids. They are characterized by distinct melting or boiling points and intrinsic

species spectra. They are appreciably soluble in organic solvents, but usually less soluble in water. The compounds containing carboxylic acid groups can be converted into their alkali metal and alkaline earth metal salts by treatment with suitable metal hydroxides, and those containing amino groups,

can be converted to their ammonium salts by treatment with organic or inorganic acids. Both of these types of salts exhibit increased solubility in water.

The properties and applicability of the compounds produced according to the invention are illustrated in the context of the tables set out below.

The compounds produced according to the invention were analyzed

with regard to two kinds of biological activity connected with their

potential use as antiatherosclerotic agents. Compounds were tested in vitro for their ability to inhibit the enzyme fatty acyl CoA:cholesterol acyltransferase (ACAT) and in vitro for serum hypolipidemic activity, as measured by their ability to inhibit lipid absorption in rats.

The compounds were tested for their ability to inhibit ACAT according to the following procedure: Rat adrenals were homogenized in 0.2 M monobasic potassium phosphate buffer, pH 7.4, and centrifuged at 1000 times gravity for 15 minutes at 5° C. The bush at the top containing the microsomal fraction that served as a source for the cholesterol-esterifying enzyme, fatty acyl CoA:cholesterol acyl-transferase (ACAT). A mixture containing 50 parts adrenal supernatant, 10 parts albumin (BSA) (50 mg/ml), 3 parts test compound (final concentration 5.2 g/ml) and 500 parts buffer was pre-incubated at 37°C for 10 minutes. After treatment with 20 parts of oleoyl CoA (14C-0.4 Ci), the mixture was incubated at 37°C for 10 minutes. A control mixture without test compound was prepared and treated in the same manner. The lipids from the incubation mixture were extracted in an organic solvent and were separated by thin layer chromatography. cholesteryl ester- the fraction was counted in a scintillation counter. This method is a modification of that described by Hashimoto, et al., Life Science, 12 (Part II), 1-12 (1973).

The results of this investigation on representative compounds prepared according to the invention are given in Table I.

Inhibition of cholesterol absorption was determined by feeding male Sprague-Dawley rats, weighing 150-170 g, with a 1% cholesterol:0.5% carbonic acid diet for 2 weeks. The diet also contained the test compounds in a dose of 0.01% of the diet. Control rats were fed the same diet without test compound. At the end of the study, the rats were euthanized by decapitation. Blood was collected, centrifuged at 1.5 kg times gravity for 10 minutes at 4°C, and the serum obtained was then analyzed for cholesterol and triglycerides enzymatically by the method of Trinder, P., Analyst, 77, 321 (1952) on a Centrifichem 400 analyzer. The livers were removed, a 0.4 g sample was taken from the center of the large loop, and the sample was subjected to saponification using 25% saturated potassium hydroxide in ethanol. The resulting neutral sterols were extracted with petroleum ether and the extract analyzed for cholesterol. The effectiveness of the compound in inhibiting cholesterol absorption is measured by the reduction of either serum cholesterol or liver cholesterol relative to the values of the control rats.

Compounds that produce 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 from this investigation are shown in table Ila.

When the compounds are used for their intended purpose, they can be combined with one or more pharmaceutically acceptable carriers, such as solvents, diluents and the like, and they can be administered orally in such preparation forms 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 elik-sir containing e.g. from approx. 20 to 50% ethanol and the like, or they can be administered parenterally in the form of sterile, injectable solutions or suspensions containing from approx. 0.5 to 5% suspending agent in an isotonic medium. These pharmaceutical preparations can, for example, contain from approx. 0.5 up to approx. 90% of the active ingredient in combination with the carrier, usually between 5 and 60%, calculated by weight.

The antiatherosclerotic effective dose of active ingredient used may vary depending on the particular compound used, the form of administration and the degree of the case being treated. However, satisfactory results are usually obtained when the compounds produced according to the invention are administered in a daily dose of approx. 2 mg to approx. 500 mg/kg body weight in the animal, preferably given in divided doses two to four times a day or in the form of prolonged release. For most large mammals, the total daily dose is from approx. 100 mg to approx. 5000 mg, preferably from approx. 100 to 2000 mg. Dosage forms that are suitable for internal use include from approx. 25 mg to 500 mg of the active compound in careful admixture with a solid or liquid pharmaceutically acceptable carrier. This dosage pattern can be adjusted to provide optimal therapeutic response. Thus, for example, several divided doses can be administered daily, or the doses can be reduced gradually as the therapeutic situation dictates. A decided practical advantage is that these active compounds can be administered orally as well as intravenously, intramuscularly or subcutaneously, if required. Solid carriers include starch, lactose, dicalcium phosphate, microcrystalline cellulose, sucrose, and kaolin, and liquid carriers include sterile water, polyethylene glycols, nonionic surfactants, and edible oils such as corn, peanut, and sesame oils, as appropriate for the condition of the active ingredient and the particular form of administration that is chosen. Excipients that are usually used in the preparation of pharmaceutical preparations can advantageously be included, such as e.g. flavoring substances, coloring agents, preservatives and anti-oxidants, for example vitamin E, ascorbic acid, BHT

and BHA.

Pharmaceutical preparations which are preferred from a preparation and administration point of view are solid preparations, particularly

tablets and capsules filled with solid or liquid. Oral administration of the compounds is preferred.

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

The pharmaceutical forms which are suitable for injection include sterile, water-based solutions or dispersions and sterile powders for the preparation of sterile injection solutions or dispersions immediately before use. In all cases, the form must be sterile and must be liquid to such an extent that it can be easily handled with an injection syringe. It must be stable under the manufacturing and storage conditions and must be preserved against the contaminating effect of microorganisms such as bacteria and fungi. The carrier can be a solvent or a dispersion medium containing, for example, water, ethanol, polyol (eg glycerol, propylene glycol and liquid polyethylene glycol). , suitable mixtures of these as well as vegetable oils.

The preparation of representative compounds is illustrated in the following examples.

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 in 50 ml of toluene is added over 15 minutes. The mixture is filtered, and the filtrate is evaporated. The residue is distilled under evaporation at 105°C and reduced pressure (250-350 µm) to give N-benzyl-N-(n-butyl)carbamyl chloride as a colorless liquid.

A solution of 3.89 g of diphenylamine in 25 ml of dimethylacetamide is added over the course of one 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 gas 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 adsorbent and acetone-hexane as eluent. After

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

Example 2

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

A solution of 5.09 g of N-phenyl-3-chloroaniline in 20 ml of toluene is added to a solution of 4.70 g of phosgene and 3.64 g of N,N-dimethylaniline in 55 ml of toluene, and the mixture is heated to 40 °C and then stirred while cooling to room temperature for 45 minutes. The mixture is extracted with water, and the organic layer is separated and evaporated to approximately 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 under reflux for 30 minutes and then washed with water,

IN 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 under evaporation at 185-190°C and reduced pressure (105 µm) to give 1-behzyl-1-(n-butyl)-3-(3-chlorophenyl)-3-phenylurea as a viscous, pale yellow liquid.

The compounds in Table II are prepared from the appropriate amines using phosgene or thiophosgene according to the procedure described in Examples 1 and 2.

Example 30

N-( 2, 4- dimethylbenzylidene)- 2, 4- dichloroaniline (starting material)

A mixture of 26.8 g of 2,4-dimethylbenzaldehyde, 32.4 g of 2,4-dichloroaniline, 0.20 g of p-toluenesulfonic acid and 150 ml of toluene is stirred under reflux with a moisture separator of the Dean-Stark type. Evaporation of the mixture gives a solid which is recrystallized from ethanol to give N-(2,4-dimethylbenzylidene)-2,4-dichloroaniline, m.p. 102-106°C.

Anilines prepared according to the method described in Example 30 are listed in Table III.

Example 4 5

N-(2, 4- dimethylbenzyl)- 2, 4- dichloroaniline (starting material)

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

Anilines prepared according to the method described in Example 45 are listed in Table IV.

Example 60

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

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

The compounds listed in Table V are prepared from suitable aryl isocyanates or aryl isothiocyanates and secondary amines by the method described in Example 60.

Example 227

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

A solution of 1.56 g of phenylchloroformate 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 1 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 24 hours. The mixture is diluted with hexane, and the fines are collected by filtration. Recrystallization from pentane gives 1-benzyl-1-(n-butyl)-3-(3-chlorophenyl)urea, m.p. 69-70°C.

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 2 5 ml of IN aqueous sodium hydroxide, stirred under reflux for 16 hours, gives cooled, acidified with IN hydrochloric acid and filtered. The solid is recrystallized from ethanol

to give 1-benzyl-1-(n-butyl)-3-(4-carboxyphenyl)urea as a white solid.

Example 229

1- benzyl- l-( 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 of boron tribromide in 40 ml of methylene chloride is stirred at room temperature for 3 days and diluted with water. The organic layer is separated, dried and evaporated. The residue is crystallized from hexane to give 1-benzyl-1-(n-butyl)-3-(2-hydroxy-3-chlorophenyl)urea, m.p. 59-62°C.

Example 230

N-(2-chlorobenzyl)-3-methoxyphenylacetamide (starting material)

A mixture of 12.5 g of 3-methoxyphenylacetic acid, 21.2 g of 2-chlorobenzylamine, 15.1 g of triethylamine, 19.3 ml of boron trifluoride etherate and 500 ml of toluene is stirred under reflux for 18 hours using a Dean-Stark moisture separator and then 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 crystallized from hexane to give N-(2-chlorobenzyl)-3-methoxyphenylacetamide as a yellow solid, m.p. 89-91°C.

Example 231

N-(n-butyl)-2-chlorobenzylamine (starting material)

A solution of 21.2 g of N-(n-butyl)-2-chlorobenzamide i

100 ml tetrahydrofuran is added under cooling to 200 ml 1M borane in tetrahydrofuran, and the mixture is stirred under reflux for 18 hours, allowed to cool and treated with

6N hydrochloric acid. The organic solvent is evaporated, and the residue is distributed between ether and aqueous sodium hydroxide solution. The ether layer is separated, dried and evaporated. The residue is distilled to give N-(n-butyl)-2-chlorobenzylamine as a colorless liquid, m.p. 65-75°C at 60 ym.

1 5 8 41 7 EXAMPLE 2 32

3-( 2, 4- dlfluorophenyl)- 1-[[ 4-( 2, 2- dimethylpropyl)-phenyl] methyl]- 1- heptylurea

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

This product was 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 was stirred at room temperature for 16 hours. Then the mixture was diluted with water and two layers were separated. The organic layer was washed sequentially with two 30 mL portions of 3N hydrochloric acid, then brine. The solution was dried over anhydrous magnesium sulfate and filtered. The filtrate was evaporated in vacuo to give 13.0 g of a gray solid. The solid was purified by preparative high pressure liquid chromatography on silica gel using ethyl acetate:hexane (1:9) as the solvent. Fractions 2, 3, 4 and 5 were combined and evaporated in vacuo to give 8.0 g of 4-(2,2-dimethylpropyl)-N-heptylbenzamide as a beige solid, mp 58-60°C.

A mixture of 7.5 g (0.026 mol) of the above amide and 20 ml (0.052 mol) of "Vitride" T [sodium-dihydrobis(2-methoxyethoxy)

aluminate (70% solution in toluene)] in 80 ml of toluene was refluxed for 4 hours and then cooled to room temperature.

The complex was decomposed by dropwise addition of 40 ml of 2.5N sodium hydroxide with stirring for 30 minutes. Two teams were separated. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and filtered. The filtrate was evaporated to dryness in vacuo to give a yellow oil. Bubble tube distillation (125°C/0.15 ml Hg) gave 6.45 g (90% yield) of 4-2,2-dimethylpropyl)-N-heptylbenzenemethane as a colorless liquid.

To a solution of 1.10 g (0.004 mol) of the above-mentioned amine in 15 ml of hexane, a solution of 0.62 g (0.004 mol) of 2,4-difluorophenyl isocyanate in 15 ml of hexane was added with stirring. The resulting mixture was stirred at room temperature for 16 hours. The solvent was evaporated in vacuo to give a colorless oil. Bubble tube distillation (140-155°C/0.15 mm Hg) afforded 1.44 g (84% yield) of the desired product as a colorless oil.

EXAMPLE 233 1 5 8 41 7

3-( 4- chloro- 2, 6- dimethylphenyl)- 1-[[ 4-( 2, 2- dimethylpropyl)

phenyl] methyl]- 1- heptylurea

To a mixture of 300 g (2.48 mol) 2,6-dimethylanllin,

2.4 liters of dichloromethane and 24 ml of ethanol cooled at 5°C in an ice bath were added anhydrous hydrogen chloride gas over a period of one hour while the temperature of the reaction mixture was maintained at 4-11°C. Chlorine gas was passed through the mixture for approx. two hours while the temperature was maintained at 5-10°C, during which time approx. 217 g of chlorine were introduced. The reaction mixture was examined several times by thin layer chromatography using 10:1 ethyl acetate:hexane as the solvent system to ensure that the reaction was complete. After completion, the mixture was flushed with argon gas and then allowed to stand at room temperature for 16 hours.

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

To a suspension of the above monohydrochloride, 371 g (1.93 mol), in 1.5 liters of diethyl ether maintained at 12-17°C in an ice bath was added 1 liter of 2M sodium acetate solution over a period of 2-3 minutes under vigorous stirring. The mixture was stirred for 30 minutes and then allowed to stand to separate the 2 layers. The organic layer was washed successively with 1 liter of water, saturated sodium bicarbonate and then water again. The organic solution was dried over anhydrous sodium sulfate and filtered. Evaporation gave 288.5 g of solid. This solid was recrystallized from 800 ml of petroleum ether and gave 229.8 g of 4-chloro-2,6-dimethylbenzenamine as colorless crystals, m.p. 47-50°C.

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. Two teams were separated. The organic layer was washed with two 40 ml portions of 3N hydrochloric acid and then with 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 ethyl acetate:hexane to give 3.8 g of (4-chloro-2,6-dimethylphenyl)carbamic acid phenyl ester as a white solid, m.p. 158-160°C.

A mixture of 1.11 g (0.004 mol) of the above phenyl ester, 1.10 g (0.004 mol) 4-(2,2-dimethylpropyl)-N-heptylbenzenemethanamine (prepared in Example 350) and 30 ml toluene was refluxed for 2 hours. The solution was cooled, washed with two 30 ml portions of 1N sodium hydroxide and then with brine. The solution was dried over anhydrous magnesium sulfate and filtered. The filtrate was evaporated in vacuo to give an oil. Bubble tube distillation (145-155°C/0.1 ml Hg) gave 1.47 g of a colorless oil which solidified on standing to give the product as a white solid, m.p. 111-113°C.

EXAMPLE 2 34

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 mol) 2,4,6-trifluoroaniline and 5.6 ml (5.4 g, 0.044 mol) N,N-dimethylaniline in 70 ml toluene was added dropwise a solution of 5.63 g (0.0359 mol) of phenylchloroformate in 20 ml of toluene. The resulting mixture was stirred at room temperature for 16 hours and gave a precipitate. The mixture was diluted with ethyl acetate and water to separate two layers. The organic layer was washed with two 50 ml portions of 3N hydrochloric acid and then with two 50 ml portions of brine. The solution was dried over anhydrous magnesium sulfate and filtered. The filtrate was evaporated in vacuo to give a solid. The solid was triturated with hexane, collected by filtration, washed with hexane and dried to give 8.38 g of (2,4,6-trifluorophenyl)carbamic acid phenyl ester as a white solid, m.p. 127-128°C in 96% yield.

A mixture of 0.97 g (0.004 mol) of the above carbamate derivative 1, 10 g (0.004 mol) 4-(2,2-dimethylpropyl)-N-heptylbenzenemethanamine (prepared in Example 350) and 40 ml toluene was refluxed for 2 hours. The resulting solution was cooled, washed with two 30 ml portions of 1N sodium hydroxide and then with brine. The solution was dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to give a pale yellow oil. Ball tube distillation (140-150°C/0.08 ml Hg) gave 1.5 g of colorless oil. A 900 mg portion of this oil was redistilled (140-150°C/0.160 mm Hg) and gave 500 mg of the product according to the Example

Claims (5)

1. Analogy method for the preparation of therapeutically active compounds of the formula where X denotes at least one substituent selected from hydrogen, Ci-C4 alkyl, hydroxy, Ci-C4 alkoxy, phenoxy, amino, halogen, trihalomethyl, Ci-C4 alkylamido and nitro, Y is selected from oxygen and sulfur, Ri and R2 are different and are independently selected from among C4-Ci 2 alkyl, C4-Ci 2 cycloalkylalkyl, C7-Ci a phenylalkyl and C7-Ci 4 phenylalkyl where the phenyl ring exhibits at least one substituent selected from Ci-Ci 0 alkyl, Ci- C 1 -C 6 alkoxy, phenoxy, benzyloxy, methylenedioxy, C 1 -C 6 alkylthio, phenyl, halogen, trihalomethyl, adamantyl and nitro; R3 is selected from hydrogen, C1-C4 alkyl, benzyl, benzyl with at least one substituent Z, naphthyl, phenyl and phenyl containing at least one substituent Z, where Z independently of X is selected from the meanings given for X, characterized in that a) an arylisocyanate or arylthioisocyanate with the formula: is reacted with a secondary amine of the formula: where X, Y, Ri and R2 have the meanings given above, or b) a compound with the formula: where Y has the meaning given above, and A and B are independently selected from halogen, Ci-C4 alkoxy, Ci-C4 alkylthio, phenoxy, 4-chlorophenoxy and 4-nitrophenoxy, is reacted with an arylamine of the formula: where X and R 3 have the meaning given above, to an intermediate with the formula after which the intermediate is reacted with a secondary amine of the formula where R 1 and R 2 have the above meaning, or c) a compound with the formula: where Y has the meaning given above, and A and B independently of each other are selected from halogen, C1-C4 alkoxy, C1-C4 alkylthio, phenoxy, 4-chlorophenoxy and 4-nitrophenoxy, is reacted with a secondary amine with the formula: where Ri and Rz have the above meaning, to an intermediate with the formula: after which the intermediate is reacted with an arylamine of the formula: where X and R3 have the meanings given above. 2. Process according to claim 1 for the production of 1-(n-heptyl)-1-[4-(2,2-dimethylpropyl)phenylmethyl]-3-(2,4-difluorophenyl)urea, characterized in that corresponding starting materials are used . 3. Process according to claim 1 for the production of 1-(n-heptyl)-1-[4-(2,2-dimethylpropyl)phenylmethyl]-3-(2,4-difluorophenyl)urea, characterized in that corresponding starting materials are used . 4. Process according to claim 1 for the production of 1-(n-heptyl)-1-[4-(2,2-dimethylpropyl)phenylmethyl]-3-(4-chloro-2,6-dimethylphenyl)urea, characterized in that corresponding starting materials are used. 5. Process according to claim 1 for the production of 1-(n-heptyl)-1-[4-(2,2-dimethylpropyl)phenylmethyl]-3-(2,4,6-trifluorophenyl)urea, characterized in that it is used corresponding starting materials.