IE47470B1 - Urea derivatives - Google Patents

Description

UREA DERIVATIVES The present invention is concerned with urea deriva· 5 tives of the general formula la in which R^3 represents halogen, trifluoromethyl, nitro or lower alkoxy, R2a rep15 resents hydrogen, halogen, trifluoromethyl, 8a nitro or lower alkoxy and R represents hydrogen, halogen or trifluoromethyl R^a, R and R being in the meta-position or para-position relative to the residue Ra; and wherein Ra represents a group of the formula CH, I33 • NH—CO—NH—C —COOR I CH, or NH >T Xa R5a 4a (a) (ba) 3l wherein R represents lower alkyl, X represents oxygen or imino, R^a represents lower alkyl and R5a represents hydrogen or lower alkyl, with the provisos (i) that where Ra signifies the group (ba) then the residue either signifies (A) one of the groups or signifies (B) the group methyl, and (ii) that where Ra signifies the group (a) and two of the groups R^a, R^a O a and R are metahalogen, the other of said groups is not hydrogen.

The expression lower alkyl and the expression lower alkoxy relate to straight-chain or branched hydrocarbon residues with up to 4 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec.-butyl and t10 -butyl; and methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec.-butoxy and t-butoxy. Halogen signifies all four halogen atoms, i.e. fluorine, chlorine, bromine and iodine.

The substituent Rla or R^a is preferably in the 38a -position or 4-position and the substituent R is preferably in the 5-position.

The novel urea derivatives of the invention have an antiandrogenio action; they can accordingly be used as medicaments, in particular for the treatment of diseases associated with increased androgenic activity, such as e.g. acne, seborrhoea, hirsutism and adenoma of the prostate. Pharmaceutical preparations including the novel derivatives of the invention are claimed in Patent Application No. 47469 of which the present Application is a Divisional Application.

Preferred antiandrogenically active preparations contain a compound of . the formula la wherein Ra represents a group (ba), especially such a group with X = oxygen, i.e. a hydantoin derivative of the formula I.

An especially preferred compound, because of its antiandrogenic action, is: N-[(3-Trifluoromethy1-4-chlorophenyl)-2-carbamoyl]-2-methylalanine methyl ester.

Some of the urea derivatives of the invention are schistosomicidally active and can accordingly be used in medicaments for the prevention and therapy of bilharzioses. These derivatives are those which contain as the active comle pound, a urea derivative of the formula Ia in which R 2a represents halogen, trifluoromethyl or nitro, R represents 4a 5a hydrogen, halogen, trifluoromethyl or nitro, R and R 8a represent methyl and R represents hydrogen.

Preferred schistosomicidally active preparations contain a compound of the formula la wherein Ra represents a group (ba), in particular such a group with X = oxygen, i.e. a hydantoin derivative of the formula I.

Especially preferred, because of their schistosomicidal action are: 3-(4-Fluoro-phenyl)-5,5-dimethyl-hydantoin; Ν-[(3-trifluoromethy1-4-chloro-phenyl)-carbamoyl]-methyl-alanine methyl ester.

The novel urea derivatives of the formula Ia can be manufactured in accordance with the invention when a) to manufacture a compound of the formula la in which Ra represents the group (a), a compound of the general formula is reacted under anhydrous conditions with a the general formula compound of X,-C-COOR32 I CH3 in which R^a, R2a, R3a and R3 have the above significance and one of the symbols X^ and X2 represents amino and the other represents the Isocyanate group -NCO or when b) to manufacture a compound of the formula Ia in which Ra represents the group (a), a compound of the general formula in which R4a, R2a and R8a have the significance 6 7 given above and R and R both represent lower alkyl, is subjected to alcoholysis using an alcohol of the formula 3 3 R OH, wherein R has the above significance, or when c) to manufacture a Ra signifies the group the general formula compound of the formula la in which (ba) with Xa = oxygen, a compound of in which Rla, R2a, R4a, RSa and R8a have the above significance and Y represents the group -OR20 or -NR8R7, wherein R8 and R7 have the above significance and R20 - 7 represents hydrogen or lower alkyl, is cyclized, or when d) to manufacture a compound of the formula Ia in which Ra signifies the group (ba) with Xa = imino, a compound of the general formula NCO VI in which Rla, R2a and R®a have the above significance, is reacted under anhydrous conditions with a compound of the general formula R4a I H2N —C CN vn I5a in which R4a and R^a have the above significance, or when e) to manufacture a compound of the formula Ia in which Ra signifies the group (ba) with Xa = oxygen, a compound of 4747 0 the general formula Ib in which Rla, R2a, R8a, R4a and R5a have the above significance, is subjected to hydrolysis, or when f) to manufacture represents the group a compound of the formula la in which R (a), a compound of the general formula Io in which Rla, R2a and R8a have the significance given above, is esterified with compounds which supply lower alkyl groups, or when g) to manufacture a compound of the formula la in which la R and/or R represents nitro, a compound of the formula Q —ι in which R and R have the significance given above and R^ and R20 have the sigla 2a niflcances given above for R and R , but at least one of the symbols R^0 and R20 representing hydrogen is nitrated.

Hereinafter, the various embodiments of the process in accordance with the invention for the manufacture of the novel urea derivatives of the formula Ia are illustrated in more detail.

The anhydrous reaction in accordance with the invention of the starting compounds of the formulae II and III leads to compounds of the formula Ia in which Ra represents the group (a). This addition reaction can be carried out without the addition of solvents, i.e. by means of a melt, or also by warming in an inert, anhydrous solvent, e.g. tetrahydrofuran, ether, dioxan, benzene or toluene. The temperature for the reaction is preferably in the range of 0°-120°C. If the reaction is carried out in a melt, it must be noted that relatively high temperatures or relatively long - 10 reaction times lead to cyclization, with formation of the corresponding hydantoin (c.f. hereinafter). The reaction should therefore be interrupted in time, which can be ac5 complished, for example, by monitoring by thin-layer chromatography.

The starting compounds of the formula IV can be manu factured by reacting a substituted benzhydroxamic acid of the general formula VIII la 2a in which R and R have the above significance, with an azirine derivative of the general formula H3C H3c IX 7 in which R and R1 have the significance given above.

The reaction proceeds successfully in an inert solvent, such as tetrahydrofuran, ether or dioxan, at room temperature or with slight warming, e.g. to 50°C.

The alcoholysis in accordance with the invention of the starting amides of the formula IV is carried out with the aid of a lower alkanol, preferably methanol or ethanol, and leads to carboxylic acid esters of the formula Ia wherein R represents the group (a). The alcoholysis is preferably carried out under acid, e.g. mineral acid, conditions, for example in methanolic or ethanolic hydrochloric acid. The reaction temperature is preferably about room temperature but, if desired, it can be i:.creased up to the boiling temperature of the reaction mixture.

The manufacture of the starting amides or esters of the formula V can be carried out analogously to the manufacture of the amides of the formula IV or of the esters of the formula Ia, from the compounds II and III. For the manufacture of a carboxylic acid of the formula V, an amide of the formula V can be dissolved in an inert organic solvent, e.g. methanol or ethanol, and the solution can be treated with an aqueous alkali, e.g. caustic soda solution or caustic potash solution, at a temperature between room temperature and the boiling point of the reaction mixture.

The corresponding carboxylic acid of the formula Ia is obtained in the customary manner by neutralization of the carboxylic acid salt formed, for example using a mineral acid.

The cyclization in accordance with the invention of the starting amides or esters of the formula V leads to hydantoin derivatives of the formula la, and in particular those wherein R signifies the group (ba) with Xa = oxygen. This cyclization is carried out, e.g. under the conditions of acid hydrolysis, preferably by treatment with an aqueous mineral acid, such as aqueous hydrochloric acid. The acid hydrolysis of amides of the formula V is advantageously carried out in an inert organic solvent, e.g. tetrahydrofuran or dioxan, and at about room temperature, it also being possible to carry out the hydrolysis at higher temperatures, e.g. up to the boiling point of the reaction mixture. The cyclization of esters of the fonnula V is preferably carried out with a water-miscible solvent, such as acetone, methyl ethyl ketone, tetrahydrofuran, dimethoxy20 ethane or dioxan. A preferred cyclization agent consists of 6-N aqueous hydrochloric acid and acetone in a weight ratio of about 1:1. The reaction temperature is preferably the boiling temperature of the reaction mixture, it also being possible to use lower reaction temperatures, e.g. down to. room temperature, with appropriately longer reaction times.

The starting esters of the formula V can likewise be cyclized by warming without solvents, i.e. by means of a melt. The temperature for this melt reaction is preferably in the range - 13 of about 100-200°C, in particular in the range of about 120-160°C. According to a preferred embodiment, this cyclization is carried out by adding the compounds of the above formulae II and III which can be used for the manufacture of the starting esters of the formula V, and by choosing an adequate reaction time or reaction temperature, the reaction proceeds to the desired cyclization product, i.e. the hydantoin of the formula Ia, without isolating the esters of the formula V intermediately formed. The reaction can be followed, for example, by thin-layer chromatography.

The anhydrous reaction in accordance with the invention of the s'arting compounds of formulae VI and VII leads to imino-imidazolidinone derivatives of the formula la, i.e. wherein Ra signifies the group (ba) with Xa = imino. The reaction can be carried out under the same conditions as the cyclization described above, using starting compounds of the formulae II and III, i.e. by means of a melt. It is also possible to heat the starting compounds of the formulae II and III with an ethereal solvent, e.g. with dioxan or dimethoxyethane.

The hydrolysis in accordance with the invention of the imino-imidazolidinone derivatives of the formula lb leads to corresponding hydantoins of the formula Ia, i.e. wherein Ra signifies the group (ba) with Xa = oxygen. The hydrolysis can be carried out, optionally with the addition of an inert -Insolvent, by treatment v/ith, e.g., a mineral acid, such as hydrochloric acid, at a temperature between room temperature and the boiling point of the reaction mixture.

The esterification in accordance with the invention of the carboxylic acid of the formula Ic leads to esters of the formula Ia wherein Ra represents the group (a). The esterification is carried out in a manner known per se by treat10 ment v/ith a lower alkanolic mineral acid, e.g. methanolic hydrochloric acid, with a lower alkyl halide, e.g. methyl iodide, and an alkali metal carbonate or bicarbonate in a solvent, such as dimethylformamide, or with diazomethane in an ethereal solvent, such as ether, tetrahydrofura 1 or dioxan The esterification temperature is in general in the range 0-50°C.

The nitration in accordance with the invention of the compounds of the formula Id leads to nitro derivatives of the formula Ia wherein Rla and/or R2a represent nitro. For this purpose, the compound of the formula Id is nitrated in a manner known per se, e.g. by treatment with nitric acid, with nitric acid and sulphuric acid,with nitric acid and glacial acetic acid or acetic acid anhydride or with an alkali metal nitrate and sulphuric acid. The nitration is preferably carried out at a low temperature, for example at about 0°C to room temperature. - 15 The following Examples are given to illustrate the invention.

Example 1 23.5 g (83 mmol) of 1-(4-chlorophenyl)-3-[1-dimethyl-carbamoyl)-1-methylethyl]-urea are dissolved in 100 ml of absolute methanol and the solution is stirred with 7.5 ml (83 mmol) of methanolic hydrochloric acid at room temperature for two days. The mixture is evaporated and, after adding 50 ml of water, the residue is extracted several times with chloroform. The chloroform solution is dried over sodium sulphate and evaporated. The residue is crystallized from chloroform-hexane: N-[(4-chlorophenyl)-carbamoyl]-2-methy1alanine methyl ester, which melts at 148-15O°C, is obtained.

Analysis: Calculated for C12H15C1N2°3 (270.72): C 53.24 H 5.58 N 10.35 Cl 13.10% Found: C 53.40 H 5.69 N 10.30 Cl 13.19% The 1-(4-chlorophenyl)-3-[1-(dimethylcarbamoyl)-1-methylethyl]-urea employed as the starting compound can be manufactured as follows: 43.7 g (0.255 mol) of p-chlorobenzhydroxamic acid are dissolved in 1300 ml of absolute tetrahydrofuran, and 33 ml - 16 (0.255 mol) of 3-dimethylamino-2,2-dimethyl-2H-azirine are added, in an argon atmosphere. After stirring the mixture at room temperature for four days, the product which has precipitated is filtered off and recrystallized from tetrahydrofuran . 1-(4-Chlorophenyl)-3-[1-(dimethyl-carbamoyl)-1-methylethyl]-urea of melting point 216-218° is obtained.

Analysis: Calculated for cj3Hi8C1N3O2: C 55.03 H 6.39 N 14.81 Cl 12.49% Found: C 55.07 H 6.53 N 14.74 Cl 12.67% 1-(4-Nitrophenyl)-3-[1-(dimethyl-:arbamoyl)-1-methy115 -ethyl]-urea, which melts at 215° (decomp.) is obtained in the same manner.

Example 2 .1 g (119 mmol) of p-chloroaniline are dissolved in 300 ml of absolute tetrahydrofuran, and a solution of 17.0 g (119 mmol) of 2-isocyanato-2-methylpropionic acid methyl ester in 150 ml of absolute tetrahydrofuran is added in the course of 15 minutes. After boiling under reflux conditions for three days, the solution is evaporated to dryness. The product which remains is crystallized twice from methylene chloride. After drying for 6 hours under greatly reduced pressure at 40°C, N-[(4-chlorophenyl)-carbamoyl]-2-methyl47470 - 17 alanine methyl ester, which melts at 147-148°, is obtained.

The following compounds can be manufactured in the same manner: N-[(3-Chlorophenyl)-carbamoyl]-2-methylalanine methyl ester (2 days under reflux conditions); m.p. 135-136°C.

N- [ (3,4-Dichlorophenyl)-carbamoyl]-2-methylalanine methyl ester (2 days under reflux conditions); m.p. 153-154°C.

N-[(4-Bromophenyl)-carbamoyl]-2-methylalanine methyl ester (2 days under reflux conditions); m.p. 143-145°C.

N-[(4-Fluorophenyl)-carbamoyl]-2-methylalanine methyl ester (1 day under reflux conditions); m.p. 132°C.

Example 3 9.75 g (50 mmol) of 5-amino-2-chlorobenzotrifluoride and 7.15 g (50 mmol) of 2-isocyanato-2-methylpropionic acid methyl ester are melted at 80°C and the melt is kept at this temperature for 30 minutes. The product which has crystallized out during this process is recrystallized from isopropanol/methylene chloride and dried under greatly reduced pressure at 50° for 20 hours. N-[(3-Trifluoromethyl-4-chlorophenyl)-carbamoyl]-2-methylalanine methyl ester, which melts at 141-142°, is obtained. - 18 Analysis: Calculated for C13H14C1F3N2O3 (338.71): C 46.10 H 4.17 N 8.27% Found: C 46.17 H 4.14 N 8.26% The following compounds are obtained in the same manner: N- [ (4-Chlorophenyl)-carbamoyl]-2-methylalanine methyl ester (in the melt at 140° for 10 minutes); m.p. 148-15O°C.

N-[(4-Trifluoromethylphenyl)-carbamoyl]-2-methy1alanine methyl ester (in the melt at 120° for 60 minutes); m.p. 156°C (sintering) 220° (decomp.).

N- [ (4-Xodophenyl)-carbamoyl]-2-methylalanine methyl ester (in the melt at 90° for 30 minutes); m.p. 148-149°C.

N-[(3-Nitro-4-chlorophenyl)-carbamoyl]-2-methylalanine methyl ester (in the melt at 100° for 30 minutes); m.p. 142-143°C.

N- [ (3-Trifluoromethylphenyl)-carbamoyl]-2-methylalanine methyl ester (in the melt at 130° for 120 minutes).

Example 4 A solution of 17.2 g (67.5 mmol) of N-[(4-fluorophenyl) -carbamoyl]-2-methylalanine methyl ester in 150 ml of 6-N agueous hydrochloric acid and 50 ml of acetone are warmed on a steam bath for 2 hours and the mixture is then - 19 concentrated. The product which has precipitated is first dried at 40°/15 Torr and then recrystallized from toluene. After drying under greatly reduced pressure at 50° for 20 hours, 3-(4-fluorophenyl)-5,5-dimethylhydantoin of melting point 166-167° is obtained.

Example 5 A mixture of 2.91 g (20 mmol) of 3-chloro-4-fluoroaniline and 3.01 g (21 mmol) of 2-isocyanato-propionic acid ethyl ester is kept at 130-140° for 9¾ hours. After crystallization from chloroform/methanol, 3-(3-chloro-4-fluorophenyl)-5-methyl-hydantoin of m.p. 174-175.5° is obtained.

Analysis: Calculated for C1OH8C1FN2O2 (242.64): C 49.50 H 3.32 N 11.55 Cl 14.61% Pound: C 49.49 H 3.18 N 11.51 Cl 14.82% Example 6 6.65 g (30 mmol) of 4-chloro-3-trifluoromethylphenylisocyanate and 4.4 g (30 mmol) of 2-amino-2-ethyl-butyric acid methyl ester are heated to 100° for 5 minutes. The crude product, 2-(N-[(4-chloro-3-trifluoromethylphenyl)carbamoyl]-amino-2-ethyl-butyric acid methyl ester), is - 20 heated in 200 ml of acetone and 600 ml of 6-N HCl on a steam bath for 8 hours. After cooling,, the mixture is extracted with methylene chloride and the extract is dried over sodium sulphate and evaporated. After crystallization of the residue from petroleum ether and from methylene chloride/ hexane, 3-(4-chloro-3-trifluoromethylphenyl)-5,5-diethylhydantoin of melting point 86-87° is obtained.

Analysis: Calculated for C^H^CIF^S^O2 (334.72): C 50.24 H.422 N 8.37% Found: C 50.40 H 4.34 N 8.27%

Claims (10)

1. CLAIMS: Urea derivatives of the general formula in which R la represents halogen, trifluoromethyl, 2a nitro or lower alkoxy, R represents hydrogen, halogen, trifluoromethyl, nitro or lower alkoxy 8a and R represents hydrogen, halogen or trifluoromethyl, R^ a , R 2a and R 3a being in the meta-position or para-position relative to the residue R a j and wherein R a represents a group of the formula CH. NH—CO—NH—C—COOR I CHor (a) 3 a wherein R represents lower alkyl, X rep4a resents oxygen or imino, R represents lower - 22 alkyl and R 5a represents hydrogen or lower alkyl, with the provisos that (i) where R a signifies the group (b a ) then the residue either signifies (A) one of the groups 5a and R represents hydrogen or C 2 ~C 4 alkyl, or signifies (B) the group methyl, and (ii) that where R a signifies the group (a) and two of the groups R la , R 2a and 8a R are metahalogen, the other of said groups is not hydrogen.
2. 2. Urea derivatives according to claim 1 wherein R a is a group of the formula (a) or (b a ), R la represents halo2a gen, trifluoromethyl or nitro, R represents hydrogen, 4a fi halogen, trifluoromethyl or nitro, R and R represent methyl and R 8a represents hydrogen.
3. 3. N-[3-Trifluoromethy1-4-chlorophenyl)-carbamoyl]-2-methylalanine methyl ester.
4. 4. 3-(4-Fluoro-phenyl-5,5-dimethy1-hydantoin.
5. 5. Process for the manufacture of urea derivatives as claimed in claim 1, which process comprises a) for the manufacture of a compound of the formula Ia in which R a represents the group (a), reacting a compound of the general formula RII R 8a under anhydrous conditions with a compound of the general formula CH COOR' CH in which R^ a , R 2a , R 8a and R 3 have the significance given in claim 1 and one of the III - 24 symbols X^ and X 2 represents amino and the other represents the isocyanate group -NCO, or b) for the manufacture of a compound of the formula la in which R a represents the group (a), subjecting a compound of the general formula IV 15 in which R la , R 2a and R 8a have the significance
6. 6. 7 given in claim 1 and R and R both represent lower alkyl, to alcoholysis using an alcohol of the general formula R 3 OH, wherein R has the significance given in claim 1, 20 or c) for the manufacture of a compound of the formula la in which R a signifies the group (b a ) with X a = oxygen, cyclizing a compound of the general formula V - 25 in which R la , R 4a , R^ a and R& have the significance given in claim 1 and Y represents the group -OR 3<3 or -NR^R 7 , wherein R® and
7. 7. 30 R have the above significance and R represents hydrogen or lower alkyl, or d) for the manufacture of a compound of the formula Ia in which R a signifies the group (b a ) with X a = imino, reacting a compound of the general formula in which R la , R 2a and R® a have the significance given in claim 1, under anhydrous conditions with a compound of the general formula VII 26 in which R 4a and R 5a have the significance given in claim 1, e) for the manufacture of a compound of the formula Ia in which R a signifies the group (b a ) with X a = oxygen, subjecting a compound of the general formula lb in which R la , R 2a , R 8a , R 4a and R 5a have the significance given in claim 1, to hydrolysis, or f) for the manufacture of a compound of the which R a represents the group (a), esterifying the general formula formula Ia in a compound of ,8a 4747ο in which R la , R 2a and R 8a have the significance given in claim 1, with compounds which supply lower alkyl groups, or g) for the manufacture of a compound of the formula Ia in which R la and/or R 2a represents nitro, nitrating a compound of the formula Id given in claim 1 and R 2-0 md R 20 have the significance given in claim 1 for R^ a and R 2a , but at least one of the symbols R 10 and R 20 representing hydrogen. 6. Process according to claim 5 for the manufacture of urea derivatives of the formula Ia, in which R 4a represents halogen, trifluoromethyl or nitro, R 2a represents hydrogen, 4a 5a halogen, trifluoromethyl or nitro, R and R represent 8a methyl and R represents hydrogen, wherein correspondingly substituted starting compounds are employed. 28 7. Process according to claim 6 for the manufacture of N-[(3-trifluoromethyl-4-chlorophenyl)-carbamoyl]-2-methylalanine methyl ester, wherein corresponding substituted 5 starting compounds are employed.
8. 8. Process according to claim 6 for the manufacture of 3-(4-fluoro-phenyl)-5,5-dimethyl-hydantoin, wherein correspondingly substituted starting compounds are employed.
9. 9. Process according to claim 5, substantially as described in any of the specific Examples.
10. 10. Urea derivatives as claimed in claim 1, whenever 15 manufactured by a process as claimed in any of claims 5 to 9.