KR820002386B1 - Process for preparing imidazolidine derivatives - Google Patents

Abstract

The imidazolidines I(R=Cl, CF3; R1=H,F, Cl; R2=H, Cl; Z=O, NH) were prepd. for use as schistosomicides and antiandrogenic substances. Thus, 3, 4-(F3C)ClC6H3NCO reacted with Me2CHCH(NH2)CN at 100≰ to give I(R=CF5, R1=Cl, R2=H, z= NH), which washydrolyzed to I(Z=O).

Description

Method for preparing imidazolidine derivatives

The present invention relates to a method for preparing an imidizolidine derivative of the general formula (I).

Where

R represents one of the following groups.

The inventors have found that the novel imidazoline derivatives of general formula (I) can be used as medicaments because they have effective therapeutic properties. For example, the compound according to the present invention can be used as a therapeutic agent for androgen secretion inhibitors, in particular, diseases caused by androgen-increasing action, such as acne jejunum, hirsutism and prostate adenoma, since the antiandrogen action is remarkable. The compounds according to the invention have anti-androgen action, of which 3- (3-chloro-4-fluoro-phenyl) -5,5-dimethylhydantoin is particularly preferred.

The imidazolidine derivative, which represents any one of the first four groups described above in which R is defined in general formula (I), can be used for the treatment and prevention of the main blood absorption layer because of its ability to eradicate schistosomiasis. have.

It is therefore an object of the present invention to provide a process for the preparation of compounds of general formula (I), characterized by cyclizing the compounds of general formula (II).

Where

R is as defined above;

Y represents a -OR ¹ or -NR ² R ³ group, a double

R ¹ represents hydrogen or lower alkyl,

R ² and R ³ both represent lower alkyl.

Acidamide, the starting material of formula (II), is a novel compound, which is also included in the scope of the present invention.

Starting material amides of Y = -NR ² R ³ in formula (II) can be prepared by reacting the substituted benzhydric acid of formula (IV) with an aziline derivative of formula (V) .

(In the formulas, R, R ² and R ³ are as defined above.)

The reaction is well performed under mild warming from room temperature to 50 ° C. in an inert organic solvent such as tetrahydrofuran, ether or dioxane.

In general formula (II), the starting ester which is Y = -OR <^10> (R <^10> is lower alkyl) can be manufactured by reacting with the compound of the following general formula (VI).

In the above formulas,

R and R ¹⁰ are as defined above;

^One of Z ¹ and Z ² represents an amino group, and the other represents an isocyanate group —NCO.

The addition reaction may be carried out without addition of a solvent, i.e. by melting or by warming in an inert anhydrous solvent, i.e. tetrahydrofuran, ether, dioxane, benzene or toluene. The reaction temperature is preferably about 0 to 120 캜. When the reaction is carried out under melting, it is cyclized to a relatively high temperature or a long time reaction to form the corresponding hydantoin of the general formula (I). To separate the starting ester (II), the reaction was measured as thin layer chromatography and blocked over time. However, it is preferable to proceed the reaction until the corresponding hydantoin of the general formula (I) is produced without separating the ester of the general formula (II) as described below.

To prepare a carboxylic acid of formula (II), i.e., a compound of formula (II) wherein Y = hydroxy, the amide of formula (II) is dissolved in an inert organic solvent such as methanol or ethanol and the solution is aqueous alkaline, i.e. Treatment with sodium hydroxide solution or potassium hydroxide solution is between room temperature and the boiling point of the reaction mixture. The corresponding carboxylic acid of general formula (II) is obtained by the conventional method of neutralizing the carboxylic acid salt produced using an inorganic acid.

Hydantoin of formula (I) is prepared by cyclization of the starting formula (II) according to the invention. This cyclization reaction is carried out under hydrolysis conditions, preferably by treatment with an aqueous inorganic acid such as aqueous hydrochloric acid.

The hydrolysis of the formula (II) amide is preferably carried out in an inert organic solvent such as tetrahydrofuran or dioxane at room temperature, and hydrolysis can be carried out even at high temperatures up to the boiling point of the reaction mixture.

Cyclization of the ester or carboxylic acid of formula (II) is preferably carried out with a water miscible solvent such as acetone, methyl ethyl ketone, tetrahydrofuran, dimethoxyethane or dioxane.

Preferred cyclizing agents are 6-N aqueous hydrochloric acid and acetone with a weight ratio of 1: 1. The reaction temperature is preferably a boiling point of the reaction mixture, and the reaction time may be increased by lowering the reaction temperature to room temperature.

The starting ester of the general formula (II) may be cyclized by heating without using a solvent, that is, by melting.

The melting temperature is preferably 100 to 200 ° C, particularly 120 to 160 ° C.

According to a preferred embodiment, the cyclization reaction is carried out by using the compounds of formulas (VI) and (VIII) which can be used for the preparation of the starting ester of formula (II), and selecting the appropriate reaction time and reaction temperature to proceed the reaction. Hydantoin of formula (I), which is a cyclization product, is produced, but the intermediate intermediate formula (II) ester is not separated. The reaction is then carried out in thin layer chromatography.

Compounds of general formula (I) are slightly crystalline solids with relatively good solubility in lower alkanols such as methanol or ethanol, dimethylsulfoxide, dimethylformamide and hexamethyl phosphate triamide. Slightly soluble in carbon tetrachloride and relatively poorly soluble in ether, benzene and water.

As mentioned above, the compound of general formula (I) is excellent in anti-androgen action. This action can be demonstrated by the following test.

10 mg / kg of formulation with 0.5 mg / kg of testosterone propionate is subcutaneously injected daily into 5 groups of 5 mice sterilized. Five control groups were either untreated or administered only testosterone propionate. The loss of weight in the abdominal prostate and semen bag is a measure of anti-androgen action.

Table 1 below shows the test results.

[Table 1]

For the chemobactericidal action of the compound according to the present invention can be proved by the following test.

Mice are infected subcutaneously with Serchia of 60 Schistozoma Manzoni. After 42 days of infection, the animals are treated with one case and with the compound to be tested for five days in a subsequent test. 5-10 are used for compound and dose (mg / kg). Ten untreated animals are used as control animals. Necropsy is carried out for 6 days or 2-3 weeks after treatment completion, respectively. Measured by dissection of the portal vein and liver of the mesenteric vein. Measure the percentage distribution of portal worms in the mesenteric vein, portal vein and liver, and record the conditions of the worms. The action of the agent can be attributed to the increase in the number of worms in hepatic blood vessels and the occurrence of lethal worms.

To make a measurement, compare the percentage of dead and live worm pairs in the hepatic vessels of infected and uninfected animals. Determination of VD ₅₀ (50% of insect repellent; capacity to kill 50% of insects) is performed by Probit method.

The summary of the test results is shown in Table 2 below.

[Table 2]

The toxicity of mice (measured after 24 hours) was measured in a similar manner, and the results are shown in Table 3 below.

[Table 3]

The products of the present invention are used in medicine, organic or inorganic, suitable for enteral or parenteral administration such as gelatin, lactose, starch, gum arabic, magnesium stearate, talc, vegetable oil, polyalkylene glycols, petrolatum and other carriers. It is used as a dosage form in combination with a carrier material. The formulations are in solid form, such as tablets or dragees, or in liquid forms, such as suspensions, emulsions. These formulations may include adjuvants such as preservatives, stabilizers, wetting or emulsifying agents, salts for adjusting the osmotic pressure or buffers, and therapeutically active substances may also be mixed.

Suitable agents include 10-500 mg of general formula (I) compound.

The dose will vary depending on the needs of the individual, but the dose of the compound is administered orally from 0.1 mg / kg to 50 mg / kg per day.

Formulations suitable as antiandrogen preparations comprise from 10 to 500 mg, preferably about 100 mg of the active substance.

The dose is orally administered 0.1 mg / kg to 10 mg / kg per day, preferably about 1 mg / kg orally. Doses are administered daily for 3 to 8 months, depending on the condition of the patient.

Formulations as schistosomiasis agents include about 100-500 mg, preferably 250 mg of active substance.

The dose is orally administered 5 mg / kg to 50 mg / kg, preferably 25 mg / kg daily.

These doses may be administered in bulk or in doses, depending on the patient's condition and expert instructions.

This dose is administered continuously for one or several days, depending on the condition of the patient.

The examples further illustrate the invention and the temperature is 0 ° C.

Example 1

14.5 g (100 mmol) 3-chloro-4-fluoroaniline and 17.2 g (120 mmol) 2-isocyanate-2-methylpropionic acid methylester are melted at 140 ° C. and the melt is held at this temperature for 6 hours. . The resulting intermediate N-[(3-chloro-4-fluoro-phenyl) -carbamoyl] -2-methylaniline methylester is not isolated. 3- (3-Chloro-4-fluoro-phenyl) -5,5-dimethylhydantoin is crystallized from isofranol / methanol / methylene chloride. Drying under dark pressure at 55 ° for 16 hours causes the product to melt at 165-166 °.

Elemental analysis: C ₁₁ H ₁₀ ClFN ₂ O ₂ (256.66)

Calculated Value: C 51.48, H 3.93, N 10.91, C 13.81%

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

Example 2

3- (3,5-Dichloro-4-fluorophenyl) -5,5-dimethyl-hydantoin (melting point 175-176 °) was prepared in the same manner as in Example 1 with 3,5-dichloro-4-fluoro- Obtained after determination in ether / petroleum ethers from aniline and 2-isocyanate-2-methylpropionic acid methylester. N-[(3,5-dichloro-4-fluorophenyl) -carbamoyl] -2-methyl-aniline methyl ester is not isolated.

Elemental analysis: C ₁₁ H ₉ Cl ₂ FN ₂ O ₂ (291.11), (291.11)

Calculated Value: C 45.39, H 3.12, N 9.62, C 24.36%

Found: C 45.55, H 3.19, N 9.57, Cl 24.58%

The next compound is obtained in the same way.

3- (3-trifluoromethyl-4-fluoro-phenyl) -5,5-dimethyl-hydantoin; Melting point: 111-112 °.

Example 3

8.00 mg (23.6 mmol) of N-[(3-trifluoro-methyl-4-chlorophenyl) -carbamoyl] -2-methylaniline methyl ester of 200 ml of 6-N aqueous hydrochloric acid solution and 20 ml of acetone The solution is warmed in a steam bath for 2 hours and the mixture is concentrated. The precipitated product is recrystallized from methylene chloride and from methylene chloride / petroleum ether. After drying for 20 hours at 50 ° under reduced pressure, 3- (3-trifluoromethyl-4-chlorophenyl) -5,5-dimethyl hydantoin having a melting point of 152 to 153 ° C is obtained.

Elemental analysis: C ₁₂ H ₁₀ ClF ₃ N ₂ O ₂ (306.67)

Calculated Value: C 47.00, H 3.29, N 9.13%

Found: C 46.89, H 3.23, N 8.93%

In the same way, the following compound is obtained.

3- (3-trifluoromethylphenyl) -5,5-dimethyl hydantoin; Melting Point: 105 to 106 °

N-[(3-trifluoromethyl-4-chlorophenyl) -carbamoyl] -2-methylalanine methyl ester used as starting compound is used as follows.

9.75 g (50 mmol) of 5-amino-2-chlorobenzotrifluorolide and 7.15 g (50 mmol) of 2-isocyanate-2-methylpropionic acid methyl ester are melted at 80 ° and held at this temperature for 30 minutes. . The product crystallized during this process is recrystallized from isopropanol / methylene chloride and dried at 50 ° for 20 hours under reduced pressure. N-[(3-trifluoromethyl-4-chlorophenyl) -carbamoyl] -2-methylalanine methyl ester having a melting point of 141 to 142 ° is obtained.

Elemental analysis: C ₁₃ H ₁₄ ClF ₃ N ₂ O ₂ (388.71)

Calculated Value: C 46.10, H 4.17, N 8.27%

Found: C 46.17, H 4.14, N 8.26%

N-[(3-trifluoromethylphenyl) -carbamoyl] -2-methyl-alanine ester used as starting compound is obtained in the same manner. (Melting at 130 ° for 120 minutes.)

Example 4

Preparation of tablets having the following composition:

The actives are mixed with lactose and corn starch and the mixture is granulated with a solution of ethyl cellulose in 16 ml of methylene chloride. The granules are dried at 40 ° and mixed with talc and magnesium stearate and the compression tableted mixture.

180 mg of tablet weight

100mg of active substance per tablet

Example 5

Preparation of tablets having the following composition:

The active material is mixed with lactose and corn starch and the mixture is granulated with 40 ml of ethyl cellulose solution in methylene chloride. The granules are dried at 40 ° and mixed with talc and magnesium stearate and compressed into a mixture.

Weight of tablet 450mg

250 mg of active substance per tablet

Example 6

Preparation of capsules of the following composition:

The active material is mixed homogeneously with lactose and corn starch and the mixture is passed through a sieve and mixed with talc and filled into gelatin capsules.

180 mg weight of the filling in the capsule

Active substance content 100 mg

Example 7

Preparation of capsules of the following composition:

The active material is mixed homogeneously with lactose and corn starch and the mixture is passed through a sieve and mixed with talc and filled into gelatin capsules.

450 mg of the weight of the filling in the capsule

250 mg of active substance

Claims (1)

A process for producing an imidazolidine derivative of the general formula (I), characterized by cyclization of a compound of the general formula (II)

In the above formulas, R represents one of the following groups;

Y represents a -OR ¹ or -NR ² R ³ group, a double R ¹ represents hydrogen or lower alkyl, R ² and R ³ both represent lower alkyl.