KR820001715B1 - Process for production of substituted 2-phenylimino-imidazolidines - Google Patents

Abstract

The process for production of substituted 2-phenylimino-imidazolidines (I; R = 2-bromo-4,5-ihydroxyphenyl, 3-chloro-4-hydroxyphenyl, 4-bromo-2,5-dihydroxyphenyl, 3,5-dihydroxyphenyl, 3,5-dibromo-4-aminophenyl, 3-methylmercaptophenyl, 3,4,5-trihydroxyphenyl, 3-bromo-4-fluorophenyl) was described. 2-(2,6-dibromo-4-hydroxymethylphebylimino)imidazoidine(II; R1=H, C1-4 alkyl) hydrochloride was reacted with 2(2,6-dibromo-4-hydroxymethylphenyl)-S-methyl-isothiurinium ildide in BuOHethylene diamine solvent. And then it was alkalized.

Description

Method for preparing substituted 2-phenylimino-imidazolidine

The present invention relates to a process for preparing novel substituted 2-phenylimino-imidazolidines of the general formula (I) exhibiting effective therapeutic properties and acid addition salts thereof.

In the above general formula

R is 2-bromo-4,5-dihydroxyphenyl, 3-chloro-4-hydroxyphenyl, 4-bromo-2,5-dihydroxyphenyl, 3,5-dihydroxyphenyl, 5 -Chloro-2,4-dihydroxyphenyl, 3-hydroxy-4-methylphenyl, 2,6-dibromo-4-hydroxymethylphenyl, 3,5-dibromo-4-aminophenyl, 3- Methyl-mercaptophenyl, 3,4,5-trihydroxyphenyl or 3-bromo-4-fluorophenyl group.

2-phenylimino-imidazolidine has already been of great interest for a long time because of their excellent pharmacological and therapeutic properties, and this type of compound has been described in several documents, for example in Belgian Patent No. 623,305, 653,933. 687,656, 687,657 and 705,944. These documents also show the essential procedure for the preparation of 2-phenyl-imino-imidazolidine.

The novel compound of the present invention can be produced by reacting a compound of the general formula (II) or an acid addition salt thereof with ethylenediamine or an acid addition salt thereof.

In the above general formula

R is as described above,

R 1 is a hydrogen atom or an alkyl group having up to 4 carbon atoms.

This reaction is carried out at a temperature of 0 to 200 ° C.

As the solvent, a polar protic solvent, a polar aprotic solvent or a nonpolar solvent can be used. However, this reaction can be carried out smoothly without using solvent at elevated temperatures. The reaction time depends on the reactivity of the raw material components used, and ranges from several minutes to several hours.

To prepare the starting compound (II), the corresponding aniline is converted to thiourea by thiocyanate. It can then be converted to isoturonium salts by alkylating agents. From these acid addition compounds, isothioureas compatible with bases can be obtained.

The 2-phenylimino-imidazolidine of formula (I) according to the present invention can be converted to its physiologically suitable acid addition salts by conventional methods.

Acids suitable for salt formation include hydrochloric acid, hydrobromic acid, hydroiodic acid, hydrofluoric acid, sulfuric acid, phosphoric acid, nitric acid, acetic acid, propionic acid, butyric acid, caproic acid, valeric acid, oxalic acid, malonic acid, succinic acid, maleic acid. , Fumaric acid, lactic acid, tartaric acid, citric acid, malic acid, benzoic acid, p-hydroxybenzoic acid, p-aminobenzoic acid, phthalic acid, cinnamic acid, salicylic acid, ascorbic acid, methanesulfonic acid, and 8-chloroteofic acid.

The novel general formula (I) compound 2-phenylimino-imida-zolidine and its acid addition salts exhibit effective therapeutic properties. Because of their strong bradycardia, they are well suited for the treatment of coronary artery disease. The effect of the compound on heart rate was tested in rabbits as well as in cats with spinal paralysis. The compound of formula (I) may be administered orally or parenterally, the dosage unit is about 0.1 to 80 mg, with 0.5 to 30 mg being preferred.

Compounds of formula (I) and acid addition salts thereof may be used in admixture with other active substances. Suitable formulations include tablets, capsules, suppositories, solutions or powders, and excipients, carriers, disintegrants or suspending agents or release delaying agents conventionally used for their preparation can be used.

The following examples illustrate the invention but do not limit its scope.

Example 1

2- (2, 6-Dibromo-4-hydroxymethyl-phenylimino) -imidazolidine hydrochloride

35.5 g of 2- (2,6-dibromo-4-hydroxymethylphenyl) S-methyl-isothiuronium iodide (0.0735 mol) are refluxed with 7.5 ml of ethylenediamine in 75 ml of butanol for 8 hours. The residue is taken up in 2N HC and the aqueous solution is extracted with ether (ether extract is discarded). The aqueous phase is then alkalined with 2N NaOH to raise the pH-value, then divided several times and extracted with ethyl acetate. The homogeneous fraction is evaporated in vacuo, the residue is taken up in methanol, adjusted to Congo-acid with hydrochloric acid and the clear solution is mixed with ether. The amorphous isolate is suction filtered and washed with ether.

After drying, 1.60 g of 5.60% of theory is obtained. Melting point 267-268 degreeC, Rf value 0.6. Fluid phase: Benzene 50, Dioxane 40, Ethanol 5, Concentrated NH ₄ OH aqueous solution 5. Carrier: Color with silica gel, potassium iodoplatinate.

2,6-Dibromo-4-hydroxy-methylaniline, which is required as a starting material, is obtained by brominating methyl-4-amino-benzoate and reducing the intermediate product to lithium aluminum hydro.

Example 2

2- (4-amino-3,5-dibromophenylimino) -imidazolidine hydrochloride

30.35 g of 2- (4-amino-3,5-dibromophenyl) -S-methyl-isobutyuronium hydroiodide (0.065 mol) was refluxed with 6.5 ml of ethylenediamine in 65 ml of methanol for 10 hours. . Thereafter, methanol is evaporated in vacuo and the viscous residue is dissolved in methanol. The solution is filtered and alkaline with 50% KOH while adding ice. In doing so, when it is stirred with ether, the imidazolidine base crystallizes and precipitates. The melting point of the imidazolidine base is from 203 to 205 캜. For the preparation of the salt, the base is dissolved in a small amount of CH ₃ OH and ether x HCl is added and mixed until the Congo-acid reaction takes place, followed by mixing with the ether, which is precipitated. After separation and drying, 3.20 g is obtained, corresponding to 13.3% of theory. Melting point: 234-236 ° C., Rf value 0.4; Fluid Bed: Benzene 50, Dioxane 40, Ethanol 5, Functional NH ₄ OH 5. Carrier: Color developed with silica gel, ultraviolet light, potassium iodoplatinate.

Example 3

2- (3-methylmercaptophenyl-imino) -imidazolidine hydrobromide

42.50 g of 2- (3-methylmercaptophenyl) -S-methyl-isothiuronium iodide (0.125 mol) was refluxed in 125 ml of CH ₃ OH with 12.5 ml of ethylenediamine for 6 hours, and the reaction mixture was vacuumed. Evaporate at The oily residue is taken up in a small amount of CH ₃ OH and precipitated with 50% KNH with ice.

The free base is again dissolved in 2N HCl and extracted with ether. Discard the acid extract, alkalinize and raise the pH to several times and extract with ether. Homogeneous ether extracts are collected, dehydrated with MgSO ₄ and purified on activated carbon.

The organic phase is adjusted to Congo-acid by 65% HBr. In this way, a white amorphous powder is precipitated. This is separated and dried to yield a yield of 6 g, corresponding to 16.7% of theory. Melting point: 147-148 degreeC. Rf value 0.3; Fluid phase: Color developed with benzene 50, dioxane 40, ethanol 5, concentrated NH ₄ OH 5, ultraviolet light and potassium iodoplatinate.

Formulation Example

Example A: Tablet

5mg active ingredient according to the present invention

Lactose 65mg

Corn Starch 130mg

Grade 2 Calcium Phosphate 40mg

Soluble starch 3mg

Magnesium Stearate 3mg

Colloidal Silithic Acid 4mg

250 mg

Produce

The active ingredient is mixed with a part of the additive, thoroughly kneaded with an aqueous solution of starch and granulated by conventional methods using a sieve. The granules are mixed with the remaining additives and compressed to produce core tablets of coated tablets weighing 250 mg. This is carried out by sucrose, talc and gum arabic in the usual way.

Example B Ampoules

1.0mg of active ingredient according to the present invention

Sodium Chloride 18.0mg

Distilled water is added to make 2.0 ml.

Produce

The active ingredient and sodium chloride are dissolved in water and filled in a glass ampoule under nitrogen.

Example C, Drops

0.02 g of active ingredient according to the invention

0.07 g of methyl-p-hydroxybenzoate

Propyl-p-hydroxybenzoate 0.03 g

Add demineralized water to make 100 ml.

Claims (1)

A method of preparing substituted 2-phenylimino-imidazolidine and its acid addition salt of general formula (I), characterized by reacting a compound of formula (II) or an acid addition salt thereof with ethylenediamine.

In the above general formula R is 2-bromo-4,5-dihydroxyphenyl, 3-chloro-4-hydroxyphenyl, 4-bromo-2,5-dihydroxyphenyl, 3,5-dihydroxyphenyl, 5 -Chloro-2,4-dihydroxyphenyl, 3-hydroxy-4-methylphenyl, 2,6-dibromo-4-hydroxymethylphenyl, 3,5-dibromo-4-aminophenyl, 3- Methylmercaptophenyl, 3,4,5-trihydroxyphenyl or 3-bromo-4-fluorophenyl group, R ¹ is hydrogen or an alkyl group having up to 4 carbon atoms.