NO801182L - PROCEDURE FOR THE PREPARATION OF IMIDAZOLINE DERIVATIVES - Google Patents

Abstract

1. Process for the manufacture of imidazolidine derivatives of the general formula see diagramm : EP0017976,P9,F1 wherein X represents imino or oxygen and R represents one of the groups see diagramm : EP0017976,P9,F2 characterized by reacting a compound of the general formula R-NH-R**4 with a compound of the general formula see diagramm : EP0017976,P9,F3 whereby in formulae II and III the one R**4 signifies hydrogen and the other R**4 signifies a COOR**5 group, wherein R**5 represents optionally substituted phenyl, and R signifies the same as above, to a compound of the general formula see diagramm : EP0017976,P9,F4 wherein R signifies the same as above, and, if desired, hydrolyzing the latter compound to a hydantoin compound of the general formula see diagramm : EP0017976,P9,F5 wherein R signifies the same as above.

Description

The present invention relates to a new method for the production of imidazolidine derivatives with the general formula

where X is imino or oxygen and R substituted phenyl with for-

2

wherein R means halogen or CF-., R hydrogen, halogen or CF^ and R 3hydrogen or halogen.

1 3

The halogen atoms that R -R can be are preferably fluorine or chlorine and can otherwise be the same or different. Substitute-13

either R -R is preferably in the meta and/or para position.

Preferred examples of R groups are 3-trifluoromethyl-4-fluoro-phenyl, 3-trifluoromethyl-4-chloro-phenyl, 3-trifluoromethyl-phenyl, 3-chloro-4-fluoro-phenyl or 3,5-dichloro -4-fluoro-phenyl as well as

.3 , 4-dichloro-phenyl.

The products obtained by the process according to the invention with formula I have valuable therapeutic properties and can therefore find use as pharmaceuticals. E.g. they are distinguished by their antiandrogenic effect and can therefore e.g. used for the treatment of diseases that are associated with increased androgen activity such as e.g. acne, seborrhea, hirsutism and pros-ta-aderioma. Particularly preferred antiandrogenically active compounds of formula i are those in which X is oxygen (compare following formula Ib); like for example. 3-(3-chloro-4-fluoro-phenyl)-5,5-dimethyl-hydantoin being particularly preferred. The imidazolidine derivatives of formula I in which R e.g. means 3-trifluoromethyl-4-fluoro-phenyl, 3-trifluoromethyl-4-chloro-phenyl, 3-trifluoromethyl-phenyl or 3-chloro-4-fluoro-phenyl are schistosmicicidally effective and can thus be used for therapy and prevention of bilharzia. Especially preferred due to its strong schistosomicidal action is 3-(3-trifluoromethyl-4-fluoro-phenyl)-5,5-dimethyl-hydantoin and 1-(3-trifluoromethyl-4-fluoro-phenyl)-5-imino-4,4-dimethyl -2-imi-dazolidinone.

The antiandrogenic effect was measured by determining the weight loss of the ventral prostate and seminal vesicles in sterilized male rats.

The schistosomicidal effect was measured by comparing the percentage of live and dead ticks in the vessels of the liver and in treated mice infected with cercariae and schistosoma mansoni as well as in infected but untreated control animals. The determination of VDj-q (vermicidal dose 50%: dose that kills more than 50% of the ground pairs) took place according to the prbbit method.

The products obtained according to the invention can be used as medicines, for example, in the form of pharmaceutical preparations containing them in admixture with a pharmaceutical organic or inorganic carrier material suitable for enteral or parenteral application such as gelatin, milk sugar, starch, gum ara -beacum, magnesium stearate, talc, plant oils, polyalkylene glycols, petroleum jelly etc. The preparations can. present in solid form, e.g. as tablets, dragées, or in liquid form, e.g. as solutions, suspensions or emulsions. They may contain auxiliaries such as preservatives, stabilisers, wetting or emulsifying agents, salts for changing dosmotic pressure or puffs. Other therapeutically active substances can also be mixed.

Appropriate pharmaceutical dosage forms contain approx. 10

- 500 mg of a compound of formula I.

The dosages are chosen depending on the individual needs. E.g. these compounds can be given in dosages of approx. 0.1 mg/kg up: to approx. 50 mg/kg per day p.o.

Usable dosage forms in antiandrogenic agents often contain approx. 10-500 mg, preferably approx. 100 mg active ingredient. The dosage is e.g. 0.1 mg/kg up to approx. 10 mg/kg per day. p.o., preferably approx. 1 mg/kg per day p.o. Appropriately, this dose is given depending on the condition of the patient approx. 3-8 months daily.

Usable dosage forms in schistosomicidal agents appropriately contain approx. 100-500 mg, preferably approx. 250 mg active substance. The dosage is e.g. about. 5 mg/kg up to approx. 50 mg/kg per day p.o., preferably 25 mg/kg p.o. per day. This amount can be given in a single dosage or in several divided dosages, depending on the patient's needs and the professional's prescription. Appropriately, this dose is given according to the patient's condition on one or more consecutive days.

The process according to the invention for the preparation of compounds of formula I is characterized by reacting a compound with the general formula

with a compound of the general formula

in which the formulas II and III one R 4 means hydrogen and the other

4 5 5

R a COOR group, in which R is optionally substituted phenyl and R has the same meaning as above, to a compound of the general formula

where R has the same meaning as above,

and, if desired, hydrolyzes the latter compound to a hydantoin compound of the general formula

where R has the meaning given above.

In order to obtain a compound of formula Ia, one can according to a first

4 5 variant react a compound of formula II with R = COOR, i.e. a compound of formula

where R and R 5 have the meanings given above, 4 with a compound of formula III with R = .H, i.e. with a compound

(α-amino-isobutyro-nitrile)

or according to another variant, a compound II with R 4 = H, i.e. a compound with formula

where R has the meaning given above with a compound III with 4 5.

R = COOR , i.e. a connection with the formula

The conversion according to the two variants conveniently takes place in solution, as the following solvents e.g. come to mind: alcohols such as lower alkanols, preferably secondary, especially isopropanoyl; ethers such as e.g. tetrahydrofuran, acid amides such as dimethylformamide. The reaction further takes place preferably in the presence of a base such as sodium bicarbonate or triethylamine, preferably using equivalent amounts of base as well as the reaction partners (Ila and Illa respectively Ilb and Illb). The reaction is conveniently carried out at room temperature. However, lower or higher temperatures, e.g. up to the solution's boiling temperature, also come into question.

The possibly desired conversion of a compound Ia into a hydantoin compound Ib can be carried out by means of hydrolysis, preferably acid hydrolysis, e.g. with mineral acid such as hydrochloric acid, at temperatures between room temperature and the boiling temperature of the reaction solution.

The compounds Ila, Ilb, Illa and Illb which are used as starting materials can, insofar as they are not known, be obtained by methods known per se. Thus the compounds Ila can be prepared by reacting an amine R-NH„ (Ilb) with a chloroformic acid phenyl ester C1-C00-R 5 and the compounds Illb by reacting such an ester (C1-C00-R ) with α-amino-isobutyronitrile (Illa) .

In the reaction according to the present invention of a compound II with a compound III, certain cases such as e.g. by using p-nitrophenyl as R 5 residue, not yet cyclic compounds with the formula

where R has the meaning stated above, act and if desired be isolated. These compounds are likewise the subject of the invention. They cycle. under the reaction conditions leading to (their formation or in the form of a melt easily to the compounds.

Yes.

In the following examples, the temperature is given in degrees Celsius.

dried over sodium sulfate and evaporated. The product is crystallized from petroleum ether. After drying at 35° under greatly reduced pressure, 3-trifluoromethyl-4-fluoro-phenyl-1-carbamic acid phenyl ester with m.p. 115-116°.

EXAMPLE 2

a) 15 ml isopropanol is added to 2.56 g (1.0 mmol) 3-chloro-4-fluoro-phenylcarbamic acid phenyl ester, 840 mg (10 mmol) sodium bicarbonate and 840 mg (10 mmol) α-aminoisobutyronitrile. After 36 hours stirring at room temperature is evaporated, the residue is taken up in 50 ml of ether and washed first with 20 ml of saturated sodium bicarbonate solution and then with water. The ether solution is extracted with 130 ml of 0.1 N hydrochloric acid and water. The aqueous solution is made alkaline (pH 8) under ice-cooling with sodium bicarbonate and extracted with methylene chloride. After drying over sodium sulphate and evaporation of the extract, the remaining product is crystallized from ether/petroleum ether. After drying at 50° under greatly reduced pressure, 1-(3-chloro-4-fluoro-phenyl)-5-imino-4,4-dimethyl-2-imidazolidinone with m.p. 135-136°.. b) The obtained .5-imino-2-imidazolidinone can be hydrolyzed analogously to example 1b with ln HCl while stirring at room temperature for 3 days to the corresponding hydantoin [3-(3-chloro-4-fluoro- phenyl)-5,5-dimethylhydantoin, m.p. 16 5-16 6°. c) The urea acid ester used as starting material can be prepared as follows: A solution of 7.25 g (50 mmol) 3-chloro-4-fluoroaniline in 90 ml abs. tetrahydrofuran is mixed with 4.2 g (50 mmol) sodium bicarbonate solution and 7.8 g (50 mmol) chloroformic acid phenyl ester and stirred for half an hour at room temperature. The solution is then shaken after adding 300 ml of methylene chloride and 80 ml of water and the organic phase is separated. After drying over sodium sulphate, the solution is evaporated and the remaining product is crystallized twice from ether/petroleum ether. After drying at 40° under greatly reduced pressure, 3-Chloro-4-fluoro-phenylcarbamic acid phenyl ester with mp 111-112° In EXAMPLE 3 a) 2.82 g (10 mmol) of 3,4-dichloro-phenylcarbamic acid phenyl ester are dissolved in 15 ml absolute tetrahydrofuran.. 0.84 g (10 mmol) of sodium bicarbonate and 0.84 g (10 mmol) of α-amino-isobutyronitrile are added and the mixture is stirred for 18 hours at room temperature. After the addition of 30 ml of water and 20 ml of saturated sodium bicarbonate solution is extracted with 170 ml ether. The solution is washed with water and extracted with 100 ml (10 mmol) 0.ln hydrochloric acid and water. The aqueous solution is made alkaline (pH 8) under ice-cooling with saturated sodium bicarbonate solution and extracted with methylene chloride. After drying this organic solution above - sodium sulfate and evaporation, the remaining product is crystallized from methylene chloride/petroleum ether. After drying at 50° under greatly reduced pressure, 1-(3,4-dichloro-phenyl)-5-imino-4, 4-dimethyl-2-imidazolidinone with m.p. 205-206°. b) The 5-imino-2-imidazolidinone obtained can be hydrolysed analogously to example 1b with 1N HCl under stirring at room temperature for 2 days to the corresponding hydantoin [3-(3,4-dichloro-phenyl)-5,5-dimethylhydantoin , m.p. 196-197].

EXAMPLE 4

a) 3.44 g (10 mmol) 3-trifluoromethyl-4-fluoro-phenylurea-acid-4'-nitrophenyl ester, 50 ml isopropanol and 0.84 g (10

mMol) of α-aminoisobutyronitrile are mixed together. After stirring for 10 minutes at room temperature, the yellow solution formed is evaporated and the remaining product is taken up with 200 ml of ether. The solution is washed with 160 ml of saturated sodium bicarbonate solution, dried over sodium sulfate and concentrated. Underneath, crystallize the product. After drying at 50° under greatly reduced pressure, N-(2-cyano-2-methylethyl)-N'-[4-fluoro-3-(trifluoromethyl)phenyl]-urea is obtained with m.p. 132-133°. Sml. formula IV.

A solution of 145 mg (0.5 mmol) of the thus obtained N-(2-cyano-2-methylethyl)-N<1->[4-fluoro-3-(trifluoromethyl)-phenyl]-urea is stirred for 8 hours and evaporated. The product is crystallized from ether/n-pentane. One obtains 1-(3-trifluoromethyl-4-fluorophenyl)-5-imino-4,4-dimethyl-2-imidazolidinone with m.p. 132-135°. b) The urea acid ester used as starting material can be obtained as follows: To a solution of 1.79 g (10 mmol) 5-amino-2-fluoro-benzotri-fluoride in 30 ml abs. tetrahydrofuran, 2.01 g (10 mmol) of chloroformate-4-nitrophenyl ester and 0.84 g (10 mmol) of sodium bicarbonate are added. After stirring for 1/2 hour at room temperature, the mixture is filtered, the filter cake is washed with ether and the filtrate and wash-. the solution is evaporated. together. The product is crystallized twice from ether/petroleum ether. After drying at 50° under greatly reduced pressure, 3-trifluoromethyl-4-fluoro-phenylcarbamic acid-4'-nitrophenyl ester is obtained with m.p. 129-133°.

EXAMPLE 5

a) A solution of a 179 mg (1 mmol) 5-amino-2-fluoro-benzo-trifluoride in 3 ml isopropanol is mixed with 84 mg (1 mmol) sodium bicarbonate and 204 mg (1 mmol) (1-cyano-l- methyl-ethyl)urea-phenyl ester and stirred for 16 hours at room temperature. After adding 20 ml of ether, the solution is washed with saturated sodium bicarbonate solution and water and extracted with 12 ml of 0.1N hydrochloric acid. The hydrochloric acid solution is made alkaline (pH 8) under ice-cooling with sodium bicarbonate and extracted with methylene chloride. After drying over sodium sulfate and evaporation of the solution, the product is crystallized from ether/petroleum ether. One obtains 1-(3-trifluoromethyl-4-fluoro-phenyl)-5-imino-4,4-dimethyl-2-imidazolidinone with m.p. 134-135°. b) The urea acid ester used as starting material can be prepared as follows: In a solution of 840 mg (10 mmol) α-aminoisobutyronitrile in 10 ml abs. tetrahydrofuran, 840 mg (10 mmol) of sodium bicarbonate are suspended. 1.56 g (10 mmol) of chloroformic acid phenyl ester are added dropwise while stirring, keeping the temperature between 20 and 30°. After a further 6 hours, filter, wash the filter cake with ether, evaporate the filtrate and washing solution and crystallize the product from acetone/petroleum ether. After drying at 50° under greatly reduced pressure, 1-cyano-1-methyl-ethyl)urea-;

o

phenyl ester with m.p. 116-118°.

EXAMPLE 6

Analogous to the above-mentioned examples 1-5, the following hydantoins can be prepared from the corresponding 5-imino-2-imidazolidinones: 3-(4-bromo-phenyl)-5,5-dimethylhydantoin; m.p. 172-173° 3-(4-trifluoromethyl-phenyl)-5,5-dimethylhydantoin) m.p. 175-176° 3-(4-chloro-phenyl)-5,5-dimethylhydantoin', m.p. 136-137°..

EXAMPLE 7

In a 2.5-liter s-flask equipped with a stirrer, thermometer, dropping funnel and calcium chloride tube, a solution of 187 g of a,a,a,4-tetrafluoro-m-tolylurea phenyl ester in 700 ml of tetrahydrofuran (dried by chromatography on Al^O ^). Under argon blowing, 52.6 g of sodium hydrogen carbonate and a solution of 52.6 g of α-aminoisobutyronitrile in 50 ml of tetrahydrofuran (dried by chromatography on Al 2 O 2 ) are added. After stirring for 40 hours at room temperature, add approx. 700 ml of ether. The ether solution is separated from the salt after 10 minutes and mixed with 300 ml of ice water. After vigorous stirring, the aqueous phase is separated and washed with 2 X 100 ml of ether. The combined ether solutions are cooled to approx. -5°C and mixed with 600 ml of ice-water and 700 ml of ice-cold ln HC1. After vigorous shaking, the acidic aqueous solution is separated and the ether solution is further washed with 3 X 100 ml of ice-cold water. The combined water solutions are adjusted slightly alkaline carefully under vigorous cooling (internal temperature approx. 3°C) and stirring with 6 5.6 g of sodium bicarbonate and extracted with approx. 5 x 1200 ml methylene chloride. The extract is dried over sodium sulfate and evaporated under reduced pressure at 40°. The remaining foamy residue dissolves in approx. 100 ml of ether and mix for crystallization with petroleum ether (low boiling). After drying for 18 hours at 45° under greatly reduced pressure, 148.8 g of 1-(3-trifluoromethyl-4-fluoro-phenyl)-5-imino-4,4-dimethyl-2-imidazolidindn (82% d. Th ., mp 133-134°) .

The crystalline, pure substance obtained is colorless...

i The 5-imino-2-imidazolidinone obtained can be hydrolyzed to the corresponding hydantoin as follows: A solution of 5.78g of 1-(3-trifluoromethyl-4-fluoro-phenyl)-5-imino-4,4-dimethyl-2 -imidazolidinone in 30 ml of 3N hydrochloric acid is kept for 4 1/2 hours at 60° (external temperature). Below that, the product is crystalline. It is filtered off, washed with deionized water and dissolved in ether. The solution is dried over sodium sulfate and evaporated. The product crystallizes when n-pentane is added. After drying for 16 hours at 50° under greatly reduced pressure, 5.7 g of 3-(3-trifluoromethyl-4-fluorophenyl)-5,5-dimethylhydantoin (98% d. Th.; m.p. 112-113°) are obtained .

The crystalline, pure substance obtained is colorless and odorless.

The urea acid ester used as starting material can be prepared as follows: In a 4.5 liter s-flask equipped with a stirrer, thermometer, dropping funnel and calcium chloride tube, a solution of 107.5 g of 5-amino-2-fluorobenzotrifluoride in 800 ml of tetrahydrofuran (dry ket by chromatography on A^O^) while stirring, 50.4 g of sodium bicarbonate are added. At an internal temperature of 22 to 23 C, a solution of 9 4.0 g of chloroformic acid phenyl ester in 200 ml of tetrahydrofuran (dried by chromatography on A^O^) is added dropwise over the course of 5 to 10 minutes and then stirred for 1/2 hour at 23°.

One adds 600 ml of methylene chloride and the mixture is washed first with 500 ml and then with 200 ml of deionized water. The aqueous solutions are extracted with 3 x 100 ml of methylene chloride. The combined methylene chloride extracts are dried over sodium sulphate and evaporated. When petroleum ether (low-boiling) is added, the product crystallizes. After 16 hours of drying at 50° under greatly reduced pressure, 175 g of 3-trifluoro-methyl-4-fluoro-phenyl-carbamic acid phenyl ester (98% d.Th.,' m.p. 115-116°) are obtained.

The crystalline substance obtained is colorless and odorless.

in

Claims (5)

1. Procedure for the production of imidazolidine derivatives with the general formula where X is imino or oxygen and R is substituted phenyl with the formula 1 2 where R means halogen or CF.,,. R. hydrogen, halogen or 3 CF^ and R hydrogen or halogen, characterized by reacting a compound with the general formula with a connection with the general formula wherein one of R 4 in formulas II and III means hydrogen and the other R <4> a COOR <5> group in which R <5> is optionally substituted phenyl. and R has the meaning given above, to a compound of the general formula i • • ■ -I. ■ .1 in which R has the above meaning, and if desired, the latter compound hydrolyzes to a hydantoin compound of the general formula . in which. R has the meaning given above. 2. Method according to claim 1, characterized in that R means 3-trifluoromethyl-4-fluoro-phenyl, 3-trifluoromethyl-4-chloro-phenyl, 3-trifluoromethyl-phenyl, 3-chloro-4-fluoro-phenyl or 3, 5-dichloro-4-fluoro-phenyl. 3. Method according to claim 1, characterized in that R means 3,4-dichloro-phenyl. 4. Process according to claims 1-3, characterized in that R 1 means p-nitrophenyl 1 . 5th; Compounds with formula characterized in that R has the one in claim 1 an given meaning.