CS207686B2 - Method of making the imidazolidinone derivatives - Google Patents

Abstract

The present invention relates to a process for the preparation of novel imidazolidinone derivatives of the general formula I, O. 7-NH R-N (AND) HN CH, -CH, in which R represents one of the groups of formulas Cl 1 It has been found that the novel imidazolidinone derivatives of the formula I obtained according to the invention have valuable therapeutic properties and can therefore be used as medicaments. So for example, these the substances have antiandrogenic activity and can therefore be used as antiandrogenic agents in particular, for the treatment of diseases associated with increased androgenic activity, such as, e.g. for example, acne, seborrhoee, hirsutism, and prostate adenoma. Those imidazolidinone derivatives of formula I wherein 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. Very particularly advantageous is due to the strong schistosomicidal effect of 1- (3-trifluoromethyl-4-fluorophenyl) -5-imino-4,4- -dimethyl-2-imidazolidihone.

Description

The invention relates to a process for the preparation of novel imidazolidinone derivatives of the general formula I,

O.

7 — NH RN (I) ^HN CH,

-CH in which

R represents one of the groups of formulas

Cl

It has been found that the novel imidazolidinone 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, particularly for the treatment of diseases associated with increased androgenic activity such as acne, seborrhoea, hirsutism and prostate adenoma. Those imidazolidinone 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. 1- (3-Trifluoromethyl-4-fluorophenyl) -5-imino-4,4-dimethyl-2-imidazolidione is particularly preferred in view of the strong schistosomicidal effect.

The imidazolidinone derivatives of the formula I can be prepared according to the invention by reacting a compound of the formula 11,

R-NCO (II) wherein

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

The reaction of the isocyanate of formula II with the alpha-aminoisobutyronitrile according to the invention under anhydrous conditions can be carried out by heating without solvent, preferably at a temperature of about 100 to 200 ° C, i.e. in the melt. It is also possible to obtain the reaction product by heating the starting materials with an ethereal solvent such as dioxane or dimethoxyethane.

Compounds of formula I are partially crystalline solids that are relatively well soluble in lower alkanols such as methanol or ethanol, 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 along with 0.5 mg of testosterone propionate per kg subcutaneously for 7 days. 2 control groups of 5 rats are not treated, or only testosterone propionate is administered. The weight loss of the ventral portion of the prostate and seminal vesicle indicates the degree of antiandrogenic effect.

The following Table I shows the results from several experiments.

Table I

Compound Ventral part of prostate mg Seminal vesicle mg control 8.0 + 0.4 6.3 ± 0.4 testosteronepropionét 59.0 + 2.0 42.0 ± 1.6 1- (3-Trifluoromethyl-4-chlorophenyl) -5-imino-4,4-dimethyl-2-imidazolidinone + testosterone propionate 29.0 ± 2.2 24.0 ± 0.6 control 14.0 ± 1.0 24.0 or 2.0 testosteronepropionét 121.0 + 13.0 100.0 ± 9.0 1- (3-Trifluoromethyl-4-fluorophenyl) -5-imino-4,4-dimethyl-2-imidazolidinone + testosterone propionate 31.0 ± 4.0 30.0 ± 2.0

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 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 pairs of worms in the mesenteric veins, in the inferior vena cava 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 worms status (living and killed) is calculated. 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 percentages of live and dead pairs of worms in the blood vessels of the liver are compared in both infected, treated animals and infected but untreated control animals. The determination of VD50 (50% vermicidal dose; 50% worm killing dose) is performed by the probit method.

Some test results are summarized in the following Table XX.

Table II

Compound VD50 mg / kg p.o.

dosed once dosed five times

- (3-Trifluoromethyl-4-chlorophenyl) -5-imino-4,4-dimethyl-2-imidazolidinone 58

1- (3-Trifluoromethyl-4-fluorophenyl) -5-imino-4,4-dimethyl-2-imidazolidinone 37

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

Table XII

Compound

1- (3-Trifluoromethyl-4-chlorophenyl) -5-imino-4,4-dimethyl-2-imidazolidinone 1- (3-Trifluoromethyl-4-fluorophenyl) -5-imino-4,4-dimethyl-2-imidazolidinone

LD50 mg / kg p.o.

312-625

312-625

The compounds of the invention may 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 stearate, 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 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 from 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 p.o., preferably about 1 mg / kg per day p. O.

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. per 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 (65 mmol) of 3-trifluoromethyl-4-chlorophenyl isocyanate and 5.5 g (65 mmol) of .alpha.-aminoisobutyronitrile are held at 100 DEG 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 a mixture of methylene chloride and petroleum ether. After 15 hours of drying under high vacuum at 50 °, - (3-trifluoromethyl-4-chlorophenyl) -5-imino-4,4-dimethyl-2-imidazolidinone melts at 148-149 °.

Analysis for C ^ HH ,ClF ^N ^O (305.69):

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

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

In the same way:

1- (3-Trifluoromethyl-4-fluorophenyl) -5-imino-4,4-dimethyl-2-imidazolidinone; mp 92-93 ° (from ether-n-pentane).

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

calculated: 49.83% C, 3.83% H, 14.53% N;

Found:% C, 49.69;% H, 3.48;% N, 14.18.

Example 2

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 ethylcellulose 4.0 mg talc 1.8 mg magnesium stearic acid salt . 0. * 2.fflg_

180.0 mg

The active ingredient is mixed with milk sugar and corn starch and granulated after addition of a solution of ethyl cellulose 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 ingredient content in 1 tablet 100 mg

Example 3

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 4

Production of capsules as follows:

active ingredient of formula X 100.0 mg milk sugar 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 filled into gelatin capsules after mixing the talc.

weight of 1 capsule content active substance content

180 mg 100 mg

Example 5

Production of capsules as follows:

active ingredient of the formula I milk sugar 250.0 mg 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, sieved and filled into gelatine capsules after mixing the talc.

weight of 1 capsule 450 mg content of active substance 250 mg which

Claims (3)

SUBJECT OF THE INVENTION A process for the preparation of imidezolidinone derivatives of the general formula I, O. y- nh R-N (I) wherein R represents one of the groups of formulas Cl CF ^₃ CF ₃ CF ₃ Cl Cl C characterized in that a compound of formula II, R-NCO wherein R is as defined above, acting under anhydrous conditions with alpha-aminoisobutyronitrile. 2. A process according to item 1 for the preparation of imidezolidinone derivatives of the general formula I, in R is one of the groups of formulas (II): 7 207686, characterized in that a compound of formula XI in which R is as defined above is used as the starting material. 3. A process according to claim 2 for the preparation of 1- (3-trifluoromethyl-4-fluorophenyl) -5-imino-4,4-dimethyl-2-imidazolidinone, characterized in that the compound of formula II is used as the starting material, wherein R is a group of formula F ₃ C Severography, n. P „závod 7, Most