CS207684B2 - Method of making the hydantoin derivatives - Google Patents

Description

(54) A method for producing hydantoin derivatives

The invention relates to a process for the preparation of novel hydantoin derivatives of the general formula I, θν (I)

R-N

-CH,

CH in which

R represents one of the groups of formulas

It has been found that the novel hydantoin derivatives of the formula I obtained according to the invention have valuable therapeutic properties; they can therefore be used as medicaments. For example, they are antiandrogenic and can therefore be used as antiandrogenic agents, especially for the treatment of diseases associated with increased androgenic activity, such as acne, seborrheea, hirsutism and prostate adenoma. A particularly preferred antiandrogenic compound of formula I is 3 - (- chloro-4-fluorophenyl) -5,5-dimethylhydantoin. Those hydantoin derivatives of formula X in which R is one of the first four groups mentioned above are effective schistosomicidally and can therefore be used for the treatment and prophylaxis of bilharziosis. Especially preferred are 3- (3-trifluoromethyl-4-fluorophenyl) -5,5-dimethylhydantoin and 1- (3-trifluoromethyl-4-fluorophenyl) -5-imino-4,4-dimethyl because of their strong schistosomicidal activity. -2-imidazolidinone.

The hydantoin derivatives of the formula I can be prepared according to the invention by cyclizing a compound of the formula II,

CH,

R-NH-CO-NH-C-COY

CH, (II) wherein

R is as defined above and

2 3

Y is -OR or -NR R, wherein r 'is hydrogen or alkyl of 1 to 7 carbon atoms and 23

R a is both C 1 -C 7 alkyl,

The starting amides of formula II, i.e. compounds of formula XI in which Y = -NR ² R ³ , can be prepared by reaction of a substituted benzhydroxamic acid of formula IV,

R-CONHOH (IV) wherein

R is as defined above, with an aziridine derivative of the formula B,

where 2 3

R and H are as described above.

The reaction is carried out in an inert organic solvent such as tetrahydrofuran, ether or dioxane at room temperature or with gentle heating, for example at 50 ° C.

The preparation of the starting esters of formula II, i.e. compounds of formula II with Y = OR ¹⁰ , wherein R ¹⁰ represents a lower alkyl group, can be carried out by reacting a compound of formula VI, R 2, (VI) in which:

R is as defined above, under anhydrous conditions, with a compound of formula VII,

CH, from _2- c-coor (VII) wherein

R ^{10 is} as defined above, and one of Z, and Z ₂ is an amino group, and the other is an isocyanate group -NCO.

This addition reaction can also be carried out without the addition of solvents, i.e. in the melt or also by heating in an inert, anhydrous solvent, for example tetrahydrofuran, ether, dioxane, benzene or toluene. The temperature for this reaction is preferably in the range of about 0 to 120 ° C. When working in the melt, care should be taken that higher temperatures and / or longer reaction times lead to cyclization to give the corresponding hydantoin of formula I. Therefore, the isolation of the starting ester of formula II should be interrupted in good time, for example by chromatography by chromatography. on a thin layer. However, it is preferred not to isolate the ester of formula II, but to allow the reaction to proceed until the corresponding hydantoin of formula I (as described below) is formed.

In order to produce a carboxylic acid of formula II, i.e. a compound of formula II with Y = hydroxy, the amide of formula II can be dissolved in an inert organic solvent such as methanol or ethanol and an aqueous alkali solution such as sodium hydroxide or potassium hydroxide is added. and allowing the reaction mixture to react at a temperature between room temperature and the boiling point of the reaction mixture. The corresponding carboxylic acid of formula II is obtained in a conventional manner by neutralizing the resulting carboxylic acid salt, for example with a mineral acid.

The cyclization of the starting materials of the formula II according to the invention is carried out, for example, under acid hydrolysis conditions, preferably by treatment with an aqueous mineral acid solution, such as an aqueous hydrochloric acid solution. The hydrolysis of the amides of the formula II is preferably carried out in an inert organic solvent, for example tetrahydrofuran or dioxane, and at temperatures around room temperature, and can also be carried out at higher temperatures, for example up to the boiling points of the reaction mixture.

The cyclization of the carboxylic acid esters of the formula II is preferably carried out in water-miscible solvents such as acetone, methyl ethyl ketone, tetrahydrofuran, dimethoxyethane or dioxane. The reaction temperature is preferably selected at the boiling point of the reaction mixture, and lower reaction temperatures, i.e. temperatures up to room temperature, with correspondingly longer reaction times can also be used. The starting esters of formula II can also be cyclized by heating without solvent, i.e., in the melt.

The temperature for this melt reaction is preferably in the range of about 100 to 200 ° C, in particular in the range of about 120 to 160 ° C. According to a preferred embodiment, the cyclization is carried out using compounds of the above formulas VI and VII, which are useful for the preparation of the starting esters of formula II, wherein the reaction proceeds without isolation of the intermediate ester of formula II up to the desired cyclization product. i.e. the hydantoin of formula I. The reaction can be monitored, for example, by thin layer chromatography.

Compounds of formula I are partially crystalline solids that are relatively well soluble in lower alkanols such as methanol or ethanol in dimethylsulfoxide, dimethylformamide and hexamethyltriophosphoric triamide, and partly also in chlorinated hydrocarbons such as chloroform, methylene chloride and carbon tetrachloride, and relatively poorly soluble in ether, benzene and water.

As already mentioned, the compounds of the formula I according to the invention have an antiandrogenic effect. This effect can be demonstrated, for example, by the following puck:

A group of 5 sterile male rats were dosed daily with 10 mg of test preparation per kg of body weight daily together with 0.5 mg of testosterone propionate per kg of subcutaneous daily for 7 days.

control groups of 5 rats are not treated, or only testosterone propionate is administered. The weight loss of the ventrile portion of the prostate and seminal vesicle indicates the degree of antiandrogenic effect.

The following Table I shows the results from several experiments.

207685.,. 4

The testosterone propionate control compound

3- (3-trifluoromethyl-4-chlorophenyl) -5,5-dimethylhydantoin + testosterone propionate control testosterone propionate

3- (3-trifluoromethylphenyl) -5,5-dimethylhydantoin + testosterone propionate 3- (3-trifluoromethyl-4-fluorophenyl) -5,5-dimethylhydantoin + testosterone propionate control testosterone propionate

3- (3,5-dichloro-4-fluorophenyl) -5,5-dimethylhydantoin + testosterone propionate

ventral part of the prostate mg 7.6 ± 0.4 s.menný vesček mg 6.3 * 0.5 47.0 * 3.1 69.0 * 3.9 25.0 i 1,0. 23.0 * 1.6 8.0 i 0,4 6.3 * 0.4 59.0 ± 2.0 42.0 ± 1.6 35.0 * 1.9 29.0 i 1.4 21.0 i 1,0 18.0 * 0.9 22.0 i 2,0 48.0 ± 4.0 184.0 * 8.0 145.0 * 7.0 72.0 * 9.0 62.0 ± 3.0

The schistosomicidal effect of the compounds of the invention as defined above can be demonstrated by the following test:

Mice are infected subcutaneously with 60 cereal cereal glands (Schistosoma mansoni). About 42 days after infection, the animals are treated once orally for 5 consecutive days with oral test compounds. 5 to 10 animals are used per compound and dose (mg / kg). 10 untreated animals are used as controls. The section is carried out 6 days or 2 to 3 weeks after the end of the treatment. The worm feathers in the mesenteric veins, the inferior vena cava and the liver are dissected and counted. The percentage distribution of pairs of worms in the mesenteric veins, the lower vena cava and the liver is calculated and the worms status (living and killed) is recorded. The effect of the preparation is manifested in an increased proportion of worms in the blood vessels of the liver and the occurrence of dead worms.

For purposes of evaluation, the percentage of live and dead pairs of worms in the blood vessels of the liver is compared in both infected, treated animals and infected but untreated control animals. The determination of VD 50 (vermicidal dose 5.0 ': dose killing 50% of the pair of worms) is performed by the probit method.

Some test results are summarized in Table II below.

TABLE IX Compound VD- ₀

,. ·. mg / kg dosed once : p.o. batch five times 3- (3-Trifluoromethyl-4-fluorophenyl) -5,5-dimethylhydantoin 47 15 Dec 3- (3-Trifluoromethyl-4-chlorophenyl) -5,5-dimethylhydantoin 59 29 3- (3-Trifluoromethylphenyl) -5,5- -dime thylhydantoin 60 32 3- (3-chloro-4-fluorophenyl) -5,5-dimethylhydantoin 68

The toxic effect on mice (observed after 24 hours) was also found and follows from Table III below.

Table III Compound

LD mg / kg p.o.

3- (3-Trifluoromethyl-4-fluorophenyl) -5,5-dimethylhydantoin 3- (3-Trifluoromethyl-4-chlorophenyl) -5,5-dimethylhydantoin 3- (3-Trifluoromethylphenyl) -5,5-dimethylhydantoin

3- (3-chloro-4-fluorophenyl) -5,5-dimethylhydantoin 3- (3,5-dichloro-4-fluorophenyl) -5,5-dimethylhydantoin, 250-2,500

000

625 to 1 250

500 to 5,000

250 to 2500

The compounds according to the invention can be used as medicaments, for example in the form of pharmaceutical preparations containing them in admixture with an organic or inorganic carrier material suitable for enteral or parenteral administration and pharmaceutical purposes such as gelatin, milk sugar, starch, acacia, magnesium salt stearic acids, talc, vegetable oils, polyalkylene glycols, petrolatum and the like. The compositions may be in solid form, for example in the form of tablets, dragees, or in liquid form, for example in the form of solutions, suspensions or emulsions. They may contain adjuvants such as preservatives, stabilizers, wetting or emulsifying agents, salts for influencing the osmotic pressure or buffers. Other therapeutically active substances may also be admixed.

Useful pharmaceutical dosage forms contain about 10 to 500 mg of the compound of formula I.

The dose is selected in accordance with individual requirements. For example, the compounds may be administered at doses of about 0.1 mg / kg to about 50 mg / kg per day, orally.

Suitably, the anti-androgen compositions useful dosage forms contain about 10 to 500 mg, preferably about 100 mg of active ingredient. The dose is, for example, about 0.1 mg / kg to about 10 mg / kg per day after, preferably about 1 mg / kg per day. day after Suitably, this dose is dosed for about 3 to 8 months daily depending on the condition of the patient.

Suitably, as schistosomieid compositions useful in dosage forms, about 100 to 500 mg, preferably about 250 mg of active ingredient are present. This dose is, for example, about 5 mg / kg to about 50 mg / kg per day p.o., preferably 25 mg / kg p.o. for 1 day. This amount may be administered in a single dose or in several sub-doses depending upon the requirement of the patient and as prescribed by the skilled artisan. Suitably, this dose is administered one or more consecutive days depending on the condition of the patient.

The following examples illustrate the invention; temperatures are given in degrees Celsius.

Example 1

14.5 g (100 mmol) of 3-chloro-4-fluoroaniline and 17.2 g (120 mmol) of 2-isocyanato-2-methyl-propionic acid methyl ester are melted at 140 ° and held at this temperature for 6 hours. The intermediate N- [(3-chloro-4-fluorophenyl) carbamoyl] -2-methylalanine methyl ester formed is not isolated. The obtained 3- (3-chloro-4-fluorophenyl) -5,5-dimethylhydantoin is crystallized from a mixture of isopropyl alcohol, methanol and methylene chloride. After drying under high vacuum at 55 ° for 16 hours, the product melts at 165-166 °.

Analysis for C, QCIFNgOg (256.66):

calculated: C 51.48%, H 3.93 45, N 10.91 45, Cl 13.81 45;

Found: C 51.51 45, H 3.78 45, N 11.11%, Cl 13.92 45.

Example 2

Following the procedure of Example 1, 3- (3,5-dichloro-4-fluorophenyl) -5, 3,5-dichloro-4-fluoroaniline and methyl 2-isocyanato-2-methylpropionate were obtained and crystallized from a mixture of ether and petroleum ether. 5-dimethylhydantoin, which melts at 175-176 °. The intermediate N - [(3,5-dichloro-4-fluorophenyl) carbamoyl] -2-methylalanine methyl ester formed is not isolated.

Analysis for C18H18FNgOg (291.11):

calculated: C 45.39 46, H 3.12 45, N 9.62 45, Cl 24.36 45;

found: C 45.55 45, H 3.19 45, N 9.57 45, Cl 24.58%.

In the same way:

3- (3'-trifluoromethyl-4-fluorophenyl) -5,5-dimethylhydantoin, m.p. 111-112 °.

Example 3

A solution of 8.00 g (23.6 mmol) of N - [(3-trifluoromethyl-4-chlorophenyl) carbemoyl] -2-methylalanine ethyl ester in 20 ml of a 6N aqueous hydrochloric acid solution and 20 ml of acetone was heated on a steam bath and then heated to 50 ° C. thicken. The precipitated product is recrystallized first from methylene chloride and then from a mixture of methylene chloride and petroleum ether. After 20 hours of drying under high vacuum at 50 °, 3- (3-trifluoromethyl-4-chlorophenyl) -5,5-dimethylhydantoin is obtained, m.p. 152-153 °.

Analysis for C ^ HH ^ ClFFNgOg (306.67):

calculated: C 47.00 45, H 3.29 45, N 9.135, found: C 46.89 45, H 3.23 45, N 8.93%.

In the same way:

3- (3-trifluoromethylphenyl) -5,5-dimethylhydantoin; mp 105-106 °.

The N - [(3-trifluoromethyl-4-chlorophenyl) carbamoyl-3-methyl-alanine methyl ester used as the starting material can be prepared as follows:

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 ° and held at this temperature for 30 minutes. The crystallized product was recrystallized from a mixture of isopropyl alcohol and methylene chloride and dried under high vacuum at 50 ° C for 20 hours. N- [(3-trifluoromethyl-4-chlorophenyl) carbamoyl] -2-methylalanine methyl ester melting at 141-142 ° was obtained.

Analysis for C ₁₃ H ₁₄ ClF ₃ N ₂ O ₃ (338.71):

calculated: C 46.10.46, N 8.27 45, H 4.17 45;

Found: C 46.17 45, N 8.26 45, H 4.14%.

The N - [(3-trifluoromethylphenyl) carbamoyl] -2-methylalanine ester used as the starting material can be prepared in a similar manner (melting 120 minutes at 130 °).

Example 4

Production of tablets of the following composition:

active ingredient of the formula I 100.0 mg milk sugar 40.0 mg cornstarch 34.0 mg ethyleelulose 4.0 mg talc 1.8 mg magnesium stearic acid salt 0.2 mg

180.0 mg

The active ingredient is mixed with milk sugar and corn starch and granulated after addition of a solution of ethylcellulose in 16 ml of methylene chloride. The granulate is dried at 40 °, mixed with talc and magnesium stearate and compressed into tablets.

weight of one tablet 180 mg content of active substance in 1 tablet 100 mg

Example 5

Production of tablets of the following composition:

active ingredient of the formula I 250.0 mg milk sugar 100.0 mg cornstarch 85.0 mg ethylcellulose 10.0 mg talc 4.5 mg magnesium stearic acid salt 0.5 mg

450.0 mg

The active ingredient is mixed with milk sugar and corn starch and the mixture is mixed with a solution of ethylcellulose in 40 ml of methylene chloride. The granulate is dried at 40 °, mixed with talc and magnesium stearate salt and compressed into tablets.

weight of one tablet 450 mg content of active substance in 1 tablet 250 mg

Example 6

Production of capsules as follows:

active ingredient of the formula I 100.0 mg milk sugar 62.0 mg cornstarch 12.0 mg talc 6.0 mg

weight of 1 capsule content active substance mg

180.0 mg

The active ingredient is mixed with milk sugar and corn starch to form a homogeneous mixture, which is passed through a sieve and, after mixing the talc, filled into gelatin capsules.

180 mg

100 ALIGN!

Example 7

Production of capsules of the following composition:

Active ingredient of the formula I Milk maize starch Talc

250.0 mg 155.0 mg

30.0 mg 15.0 mg

450.0 mg

The active ingredient is mixed with milk sugar and corn starch to form a homogeneous mixture, which is passed through a sieve and filled into gelatin capsules after mixing the talc.

Claims (4)

SUBJECT OF THE INVENTION A process for the preparation of hydantoin derivatives of the general formula I O — — NH R-N (I) -CH in which R represents one of the groups CH, €> · ^or -O- q. , or ^F 3 ^{C F} 3 ^C Cl Cl Cl f-λ characterized by cyclizing the compounds of formula II, CH 2 R-NH-CO-NH-C-COY CH, (II) wherein R is as defined above and Y is -Of 'or -NR ² R 6 in which R ¹ is hydrogen or C 1 -C 7 alkyl and 2 R ^J and R are both alkyl of 1 to 7 carbon atoms. 2. The process of item 1 for producing a hydantoin derivative of the formula I wherein R is one of _F / y, _c , / y, Cv. fZV FgC FgC FgC Cl, characterized in that a compound of formula II is used as the starting material, wherein R is as defined above and Y is as defined in point 1. 9. 3. The method of item 2 for the preparation of 3- (3-chloro-4-fluorophenyl) -5,5-dimethylhydaatoin, characterized in that a compound of formula II wherein R is a group of formula Cl and Y have the meaning given in point 1. 4. A process according to item 2 for the preparation of 3- (3-trifluoromethyl-4-fluorophenyl-5,5-dimethylhydantoin), wherein the starting material is a compound of formula II wherein R is a group of formula and Y is the meaning referred to in point 1.