CS207685B2 - 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 the novel hydantoin derivatives of the general formula I, in which:

R represents one of the groups of formulas

^f 3 ^{C f} 3 ^C

f ₃ c Cl Cl

It has been found that the novel hydantoin derivatives of the formula I obtained according to the invention have valuable therapeutic properties and can therefore be used as medicaments. For example, they are antiandrogenic and can therefore be used as antiandrogenic agents, in particular for the treatment of diseases associated with increased androgenic activity, such as acne, seborrhoea, hirsutism and prostate adenoma. A particularly preferred antiandrogenic compound of formula I is 3- (3-chloro-4-fluorophenyl) -5,5-dimethylhydantoin. Those hydantoin derivatives of the formula I in which R represents 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.

According to the invention, the hydantoin derivatives of the formula I can be prepared by hydrolyzing a compound of the formula II,

O.

y-nh

R-N

- ^ch 3 ^HN CH ₃ in which

R is as defined above.

The imidazolidinone of formula II, which is used as the starting material, can be prepared by reacting an isocyanate of formula III,

R-NCO (III) wherein

R is as defined above, with alpha-aminoisobutyronitrile, under anhydrous conditions.

This reaction can be carried out by heating without solvent, preferably at temperatures in the range of about 100 to 200 ° C, i.e. in the melt. It is also possible to obtain the starting materials of formula II by heating the reactants with an ether solvent, for example dioxane or dimethoxyethane.

The hydrolysis according to the invention can optionally be carried out by adding, for example, an inert solvent by treatment with, for example, a mineral acid such as hydrochloric acid at a temperature between room temperature and the boiling point of the reaction mixture.

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 sparingly 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 experiment:

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 subcutaneously 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 of several experiments:

Table I

compound ventral part of the prostate mg setnenný pouch mg, control 7.6 ± 0.4 6.3 ± 0.5 testosterone propionate 3- (3-trifluoromethyl-4-chlorophenyl) -5,5-dimethylhydantoin + 69.0 3 3.9 47.0 ± 3.1 + testosteronepropionét 25.0 ± 1.0 23.0 ± 1.6 control 8.0 ± 0.4 6.3 * 0.4 testosteronepropionét 3- (3-Trifluoromethylphenyl) -5,5-dimethylhydantoin + testosterone- 59.0 ± 2.0 42.0 ± 1.6 propionate 3- (3-Trifluoromethyl-4-fluorophenyl) - 35.0 ± 1.9 29.0 ± 1.4 -5,5-dimethylhydantoin + testosterone propionet 21.0 ± 1.0 18.0 ± 0.9 control 22.0 ± 2.0 48.0 ± 4.0 testosteronepropionét 3- (3,5-Dichloro-4-fluorophenyl) -5,5-dimethylhydantoin + pasta 184.0 * 8.0 145.0 - 7.0 steronpropionét 72.0 ± 9.0 62.0 or 3.0 Schistosomicidal effect as defined above of the compounds of the invention can be demonstrate

by the following test:

Mice are infected subcutaneously with 60 cerebral cereal ceramics (Schistosoma mansoni).

About 42 days post-infection, animals are treated orally with test compounds for 1 consecutive day for 5 consecutive days. 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 pairs in the mesenteric veins, in the lower hollow vein and 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 condition of the Worms (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 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 50 dose, killing 50% of pairs of worms) is performed by the probit method.

Some test results are summarized in Table II below.

Table II

compound ^TO 50 mg / kg po dosed once dosed 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-dimethylhydantoin 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 50 mg / kg po 3- (3-Trifluoromethyl-4-fluorophenyl) - -5,5-dimethylhydantoin 1 250 to 2 500 3- (3-Trifluoromethyl-4-chlorophenyl) - -5,5-dimethylhydantoin 5 000 3- (3-Trifluoromethylphenyl) -5,5- -dimethylhydantoin 625 to 1 250 3- (3-chloro-4-fluorophenyl) -5,5- -dimethylhydantoin 2,500 to 5,000 3- (3,5-dichloro-4-fluorophenyl) -5,5- -dimethylhydantoin 1 250 to 2 500

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 enteric or parenteral administration and pharmaceutical purposes such as gelatin, milk sugar, starch, acacia, magnesium stearic acid salt, 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 excipients such as preservatives, stabilizers, wetting or emulsifying agents, salts for affecting 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 dosages of about 0.1 mg / kg to about 50 mg / kg per day, orally.

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

Γ

As schistosomicidal compositions, the dosage forms useful herein suitably contain about 100 to 500 mg, preferably about 250 mg, of the active ingredient. 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 mg (0.2 mmol) of 1- (3-trifluoromethyl-4-chlorophenyl) -5-imino-4,4-dimethyl-2-imidazolidinone was dissolved in 4 ml of a 0.1N aqueous hydrochloric acid solution and 2 ml were added. water. The slowly precipitating white needles are filtered off after 20 hours, washed with water, and dried under high vacuum at 65 ° for 2 hours. This gives 3- (3-trifluoromethyl-4-chlorophenyl) -5,5-dimethylhydantoin which melts at 156-157.5 °.

1- (3-Trifluoromethyl-4-chlorophenyl) -5-imino-4,4-dimethyl-2-imidazolidinone, which is used as starting material, may be prepared as follows:

14.5 g (65 mmol) of 3-trifluoromethyl-4-chlorophenylisocyanate and 5.5 g (65 mmol) of alpha-aminoisobutyronitrile are held at 100 ° for 20 minutes. The viscous oil obtained is chromatographed on 500 g of silica gel (particle size about 0.06-0.2 mm) for further purification using methylene chloride / methanol as eluent. The product obtained is crystallized from methylene chloride / petroleum ether. After 15 hours of drying under high vacuum at 50 °, 1- (3-trifluoromethyl-4-chlorophenyl) -5-imino-4,4-dimethyl-2-imidazolidinone melts at 148-149 °.

Analysis for .delta.

calculated: C 47.15 «, H 3.63,, N 13.75,, Cl 11.60;;

Found: C 47.11 «, H 3.66«, N 13.84 «, Cl 11.86«.

In the same way:

- (3-trifluoromethyl-4-fluorophenyl) -5-rimino-4,4-dimethyl-2-imidazolidinone; mp 92-93 ° (from ether-n-pentane).

Analysis for C ^ HH ^F ^N ^O (289.23):

calculated found:

C 49.80 «, C 49.69«,

H, 3.83, N, 14.53; H, 3.48%; N, 14.18%.

Example

The following compounds can be obtained in an analogous manner to that described in Example 1:

3- (3-chloro-4-fluorophenyl) -5,5-dimethylhydantoin (mp 165-166 °), 3- (3,5-dichloro-4-fluorophenyl) -5,5-dimethylhydantoin (mp 175-176 °) 3- (3-trifluoromethyl-4-fluorophenyl) -5,5-dimethylhydantoin, (mp 111-112 °), and 3- (3-trifluoromethylphenyl) -5,5-dimethylhydantoin (mp 105-106 °).

Example 3

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 ethyleellulose 4, , 0 mg talc  1, , 8 mg magnesium salt of stearic acid O, , 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 ´ active substance content 100 mg

Example 4

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 ethyleellulose 10.0 mg talc 4,5 mg magnesium salt of stearic acid 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 and compressed into tablets.

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

Example 5

Production of capsules as follows:

the active ingredient of the formula I is milk sugar 100.0 mg 62.0 mg cornstarch 12.0 mg talc 6.0 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, is filled into gelatin capsules.

weight of capsule content active substance content

180 mg 100 mg

Example 6

Production of capsules as follows:

active ingredient of the formula I 250.0 mg milk sugar 155.0 mg cornstarch 30.0 mg talc 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, after mixing with talc, filled into gelatin capsules.

weight of filled capsule 450 mg active ingredient content 250 mg

Claims (4)

SUBJECT OF THE INVENTION A process for the preparation of hydantoin derivatives of the general formula I, O _K RN I 0-ch ₃ ch ₃ (I) wherein R is a radical of formula Cl Cl Cl characterized in that the compound of formula (II), O 7 — NH R-N (II) wherein R is as defined above, subjected to hydrolysis. 2. A process according to item I for the preparation of a hydantoin derivative of the formula I in which R is characterized in that the starting material is a compound of the formula II in which R is as defined above. 3. The process of item 2 for the preparation of 3- (3-chloro-4-fluorophenyl) -5,5-dimethylhydantoin, wherein the starting material is a compound of formula II wherein R is a group of formula Cl 4. The method of item; characterized in that it represents a group of the formula for the preparation of 3- (3-trifluoromethyl-4-fluorophenyl) -5,5-dimethylhydanto, a compound of the formula IX in which R is used as the starting material