KR800000504B1 - Process for preparing 2,6-disubstituted 2-phenyl-imido-imidazolidines - Google Patents

Abstract

Title compd. (I, Z = 2-ethyl-6 methylpheny1, 2-chloro-6-fluouophenyl, 2, 6-ditrifluoromethoxyphenyl, 2-bromo-6-chloro-phenyl, 2-chloro-6-trifluoro-methylphenyl or 2-fluoro-6-trifluoromethylphenyl) and its salt, useful as anti-hypertensive, was prepd. by treating compd. II (X and Y are same or not, halogen, sulfohydryl, hydroxy, amino, C1-4 alkylthio, alkoxy) with ethylenediamine. Thus, 332 g N-(2-ethyl-6-methylphenyl) -s-methylisothouronium hydroiodide and 96 ml ethylenediamine were heated to 150≰C for 20 min in oil bath gave 32.4 g 2-(2-ethyl-6-methylphenylamino)-imdazolidine.

Description

Method for preparing 2,6-disubstituted 2-phenylamino-imidazolidine

The present invention relates to a method for preparing 2,6-disubstituted 2-phenylamino-imidazolidine of the following structural formula (I) and various physiologically poisonous acid addition salts thereof having a blood pressure lowering action as various antihypertensive agents.

Z is 2-ethyl-6-methylphenyl, 2,6-difluorophenyl, 2-chloro-6-fluorophenyl, 2,6-dimethoxyphenyl, 2,6-dihydroxyphenyl, 2 , 6-ditrifluoromethoxyphenyl, 2-bromo-6-methylphenyl, 2-bromo-6-chlorophenyl, 2-chloro-6-trifluoromethylphenyl, or 2-fluoro-6-trifluoro Methylphenyl.

For a long time 2-phenylamino-imidazolidine has attracted great attention for its excellent pharmaceutical and therapeutic action.

Compounds of this type are therefore often published in the literature and are described, for example, in Belgian patents 623,305, 653,933, 687,656, 187,657 and 705,944.

It also describes the preparation of 2-phenylamino-imidazolidine.

Recent tests have shown that central α-adrenergic stimulation is due to the structure of 2-phenyl-imidazolidines. Therefore, it was found that only such derivatives exhibited an excellent blood pressure lowering effect and phenyl and imidazolidine had non-planar structures with each other.

In this case, the free rotation of the phenyl ring around the C-N single bond is inhibited, and the two rings are almost perpendicular to each other.

That is, by reacting with 2-phenylamino-imidazolidine to form the orthoplane by substituting the ortho position of the aromatic moiety of the formula:

The macroatomic and atomic groups in this position prevent the free rotation of the phenyl ring around the C-N single bond, respectively, thus eliminating the possibility that the two rings are in the same planar position.

The compound of formula (I) according to the present invention is prepared by reacting the following compound of formula (II) with ethylenediamine and optionally converting the product obtained above into its physiologically toxic acid addition salt.

Wherein Z is as defined above and X and Y are the same or different from each other halogen atoms (preferably chlorine), sulfhydryl, alkylthio, alkoxy, hydroxy, amino or nitroamino groups wherein the alkyl group is 1- It contains four carbon atoms.

Structural formula (II) compounds as starting materials are, for example, isocyanide dihalide (especially isocyanide dichloride), thiourea, O-alkyl ureas (and acid addition salts thereof), S-alkylthioureas (and their Acid addition salts), guanidines and their acid addition salts, carbamic acid esters, thiocarbamic acid chlorides, alkylthio-carbamic acid chlorides or nitroguanidines, of which alkyl groups contain 1-4 carbon atoms.

This reaction is carried out at 0 ° to 200 ° C. according to the X and Y groups, and a polar protic, a polar aprotic or a nonpolar solvent may be used as the solvent.

Depending on the X and Y groups, this reaction can be carried out well without using a solvent at elevated temperatures. When one or both of the X and Y groups represent a halogen atom, it is preferable to use an acid binder in the reaction, and the reaction time may vary from several minutes to several hours depending on the reactivity of the starting materials.

The compound of formula (II) used as starting material is obtained according to one of the following schemes.

Scheme 1

Scheme 2

According to Scheme (I), the desired benzoic acid and its isomers are obtained and separated by column chromatography (silica gel).

Synthesis of 2,6-difluoromethylphenyl-lithium, which is an intermediate step in preparing 2,6-ditrifluoromethylaniline, is described, for example. Hallas et al. J. Soc. Dyers & Colourists 1970, 86, 200.

2-phenyl-aminoimidazolidine of formula (I) prepared according to the present invention can be converted into their physiologically toxic acid addition salts according to conventional methods. Acids suitable for such salt formation include hydrochloric acid, hydrobromic acid, hydroiodic acid, hydrofluoric acid, sulfuric acid, phosphoric acid, nitric acid, acetic acid, propionic acid, butyric acid, caponic acid, valeric acid, oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid. , Lactic acid, tartaric acid, citric acid, malic acid, benzoic acid, P-hydroxy benzoic acid, P-aminobenzoic acid, phthalic acid, cinnamic acid, salicylic acid, ascorbic acid, methanesulfonic acid, ethanephosphoric acid, 8-chlorothiophylline and the like. .

This novel compound and acid addition salts thereof have an effective therapeutic action, in particular, lowering blood pressure and thus can be used for treating various hypertension. The compound of formula (I) may be administered orally or parenterally and the dosage is 0.1-80 mg, preferably 0.5-30 mg.

The compound of formula (I) and acid addition salts thereof can also be used with other active ingredients. Suitable formulations include tablets, capsules, suppositories, solutions or powders and conventional excipients, carriers, disintegrants, lubricants or substances for delaying release may be used to prepare them.

The following examples are illustrative of the invention in detail and do not limit the scope of the invention.

Example 1

2- (2-ethyl-6-methylphenylamino) -imidazolidine

322 g (0.96 mol) of N- (2-ethyl-6-methylphenyl) -S-methylisothiouronium hydroiodide are heated to 150 ° C. for 20 minutes with stirring in 96 ml of ethylenediamine and an oil bath. Excess ethylenediamine is evaporated in vacuo, then the viscous residue is taken up in a small amount of methanol and the base is precipitated with 50% potassium hydroxide solution while simultaneously adding water. This proceeds while cooling with ice. After decanting the aqueous phase, the oily base is dissolved in chloroform, the dichloroform solution is dehydrated with anhydrous magnesium sulfate, and then evaporated in vacuo.

The solution obtained by dissolving the residue in dilute hydrochloric acid is extracted with ether at various pHs (by adding sodium hydroxide solution). Pure fractions are collected by thin layer chromatography and dried by vacuum evaporation. This was again purified by chromatography on Al ₂ O ₃ (eluent with chloroform) to give 32.4 g (16.6% of theory) of high purity imidazoline base with melting point of 134-136 ° C.

Example 2

2- (2,6-difluorophenylamino) -imidazolidine

5.8 g of thiourea obtained from 2,6-difluoroaniline (J. of Medical Chemistry 11 / 4,814 (1968) (melting point 148-149 ° C.) was 2.8 ml of methyl iodide in 30 ml of anhydrous methanol. The mixture was heated at reflux for 3 hours, and N- (2,6-difluorophenyl) -S-methyl-isothiouronium hydroiodide (in quantitative yield) having a melting point of 150 ° C. was obtained from 3.1. Methyl ethylenediamine (150%) is heated in an oil bath with stirring to 155 to 160 ° C. Methyl mercaptan and ammonia run off 15 minutes later, the reaction product is taken up in 20 mL of methanol and purified with activated carbon.

After filtration the clear pale yellow solution is alkalized with 50% potassium hydroxide solution and then the separated solid imidazoline base is aspirated. After washing with water and drying, thin layer chromatography gave 1.3 g (21.4%) of pure base. (Melting point 169-170 ° C.).

Hydrochloride of 2- (2,6-difluorophenylamino) -imidazolidine dissolves at 248-250 ° C. which is white and soluble in water and alcohol.

Example 3

2- (2-Chloro-6-fluorophenylamino) -imidazolidine

2-chloro-6-fluoro-aniline hydrochloride at melting point 179-180 ° C. obtained according to Scheme 1 was reacted with ammonium rodanide in chlorobenzene to give N- (2-chloro-6-fluorophenyl (-thiourea (melting point). 135 ° C.) and react with methyliodide to give N- (2-chloro-6-fluorophenyl) -S-methyl-isothiouronium hydro iodide 13.2 g of isothiouronium hydro Iodide is heated with 3.8 ml of ethylenediamine (150%) in an oil bath with stirring for 15 minutes at 150-160 ° C. After cooling the clear and uniform melt, it is dissolved in about 30 ml of methanol and the solution Purification with activated charcoal is followed by precipitation of the imidazoline base with 50% potassium hydroxide solution (cooling with ice).

Aspiration filtration, washing with water and drying gave 1.8 g (22.2% of theory) of the title compound at melting point of 139-142 ° C. Hydrochloric acid having a melting point of 260 to 262 DEG C is obtained according to a conventional method, and purified by thin layer chromatography.

Example 4

2- (2,6-dimethoxyphenylimino) -imidazolidine

1.77 g of N- (2,6-dimethoxyphenyl) -S-methylisothiouronium hydroiodide (melting point 193-195 ° C.) with 0.5 ml of ethylene diamine in 10 ml of n-butanol for 1 hour Reflux to obtain 0.5 g of 2- (2,6-dimethoxyphenylimino) -imidazolidine hydroiodide at melting point 207-208 ° C.

It is difficult to dissolve in water but readily soluble in ethanol and dimethyl sulfoxide.

Preparation of Imidazolidine Bases

The 1.5 g hydroiodide obtained above is dissolved in 75 ml of water and the imidazolidine base is liberated using 5N sodium hydroxide solution. This is initially dissolved. It is only salted with ordinary salts and then separated into solid, which is taken up in chloroform to separate the chloroform solution, dehydrated with anhydrous magnesium sulfate and evaporated in vacuo to a small amount. Anhydrous ether is added to crystallize the base.

Yield: 0.5 g, Melting point: 155-157 ° C

Example 5

2- (2,6-di-trifluoromethylphenylamino) imidazolidine

1.25 g (0.004 mole) of N- (2,6-di-trifluoromethylphenyl) -isocyanide dichloride [2,6-di- from benzene, 1,3-di- (trifluoromethyl) -benzene (Trifluoromethyl) -benzoic acid (melting point 136-138 ° C.), 2,6-di- (trifluoromethyl) -benzamide (melting point 200-202 ° C.), 2,6-di- (trifluoromethyl ) -Aniline and 2,6-di- (trifluoromethyl) -formaniline (made via melting point 179-181 ° C.) to 10 ° C. with 2.7 g of ethylenediamine in 15 ml of anhydrous ether. React.

After isocyanide dichloride is completely added, it is left to stand at room temperature and further stirring is continued for 30 minutes. The reaction mixture is evaporated to dryness in vacuo and then the residue is dissolved in dilute hydrochloric acid. For purification, the solution is extracted twice with ether at pH 5.5 and then the aqueous imidazoline hydrochloride solution is alkaline with 5N sodium hydroxide solution, simultaneously adding petroleum ether and then crystallized.

After aspiration, it is washed with a small amount of water and petroleum ether and dried to obtain a slightly contaminated imidazolidine base.

Melting point 170-174 DEG C, Yield: 360 mg (30.2% of theory) Chromatography using a mixture of methanol: acetone: chloroform = 6: 3: 15 as eluent on silica gel to purify the crude base was carried out with pure 2- ( Obtain 2,6-di-trifluoromethylphenylimino) -imidazolidine.

Melting point 177 to 178 ° C

Example 6

2- (2-Bromo-6-methylphenylimino) -imidazolidine

2-bromo-6-methylaniline synthesized according to Scheme 2 was reacted to obtain N- (2-bromo via N- (2-bromo-6-methylphenyl) -thiourea (melting point 166-168 ° C). -6-methylphenyl) -S-methyl isothiouronium hydroiodide was obtained and 17.4 g (0.045 mole) was refluxed with 4.5 ml of ethylenediamine in 50 ml of ethylene glycol-monomethyl ether for 10 hours. . The reaction mixture is evaporated to dryness in vacuo, the semisolid residue is dissolved in methanol and treated with activated charcoal and the methanolic solution is then alkalized with 50% potassium hydroxide solution.

The precipitated imidazolidine base is suction filtered and dissolved in dilute hydrochloric acid for further purification, and then the hydrochloric acid solution is extracted with ether with various pH values.

Fractions obtained almost thinly by thin layer chromatography are collected and evaporated to carbonic anhydride over magnesium sulfate, and the residue is then crystallized by stirring with a small amount of anhydrous ether.

Yield: 2.6 g, Melting point: 140-145 ° C.

Column chromatography on silica gel with methanol: acetone: chloroform = 6: 3: 15 as eluent to convert to high purity base. The melting point of the compound thus purified is 142-144 ° C.

Example 7

2- (2-Bromo-6-chloro-phenylimino) -imidazolidine hydrochloride

The required 2-bromo-6-chloroaniline was obtained from 3-chloro-2-nitrobenzoic acid corresponding to Scheme 2.

3-chloro-2-nitro-benzoylchloride (melting point 62-64 ° C.)

3-chloro-2-nitro-benzamide (melting point 200-203 ° C.),

3-chloro-2-nitro-aniline (melting point 60-65 ° C.) and

Prepared by reduction with aniline via 3-chloro-2-nitro-bromobenzene.

2-bromo-6-chloro-aniline is reacted with methyl iodide to give N- (2-bromine via N- (2-bromo-6-chlorophenyl) -thiourea (melting point 148-153 ° C.). Mo-6-chlorophenyl) -S-methylisothiouronium hydroiodide was obtained and 8.3 g (0.021 mol) of this hydro iodide was combined with 2.1 ml of ethylenediamine in 20 ml of n-butanol for 16 hours. Reflux with stirring. It is ice-cooled to separate the precipitate, suction filtered and the mother liquor is evaporated to dryness. Dissolve the remaining oil in dilute hydrochloric acid, extract this hydrochloric acid solution, and discard the ether extract. The aqueous phase is extracted with ether at various pHs and the pure fractions obtained by thin layer chromatography are collected and vacuum evaporated dehydrated on anhydrous magnesium sulfate. The residue is dissolved in ether and precipitated hydrochloride with etheric hydrochloric acid followed by suction filtration and drying.

Yield: 1.5 g, melting point 297 to 300 ° C

Example 8

2- (2-Chloro-6-trifluoromethylphenylimino) -imidazolidinehydrochloride

9 g of N- (2-chloro-6-trifluoromethylphenyl) -isocyanide dichloride [2-chloro-6-trifluoromethyl-benzoic acid from 3-chloro-benzotrifluoride according to Scheme 1 Melting point 120 to 123 ° C.), 2-chloro-6-trifluoromethyl-aniline (oil phase) and 2-chloro-6-trifluoromethyl-formanilide (melting point 167 to 170 ° C).] Is reacted with 21.6 mL of ethylenediamine (10-fold excess) at 10 ° C. in 100 mL of anhydrous ether. After 30 minutes, the reaction mixture is evaporated in vacuo to dryness and the residual oil is dissolved in dilute hydrochloric acid. After extraction twice with ether, the aqueous phase is separated and treated with activated charcoal, followed by extraction with ether with increasing pH (alkaline with sodium hydroxide solution). Pure ether fractions obtained by thin layer chromatography are combined and dried, and imidazolidine hydrochloride is precipitated by mixing with etheric hydrochloric acid until the reaction of Congo acid, followed by pure 2- (2-chloro-6-trifluoromethylphenylimino). Obtain imidazolidine hydrochloride.

Yield: 3.2 g (32.9%), melting point 277-279 ° C,

The white crystalline material is dissolved in water and lower alcohol.

Example 9

2- (2-Fluoro-6-trifluoromethyl-phenylimino) -imidazolidine-hydrochloride

2-fluoro-6-trifluoromethyl benzoic acid (melting point 81 to 84 ° C.), 2-fluoro-6-trifluoromethyl aniline (oil), 2 as an intermediate according to Scheme 1 in the same manner as in Example 8 Isocyanide dichloride obtained via -fluoro-6-trifluoromethylformanilide (melting point 116-118 ° C.) is reacted with ethylene diamine to afford the title compound.

Yield: 44.9%, melting point 262 to 264 ° C

The following example is a preparation example for making a compound obtained according to the present invention into a pharmaceutical preparation.

Preparation Example 1: Purification

2- (2,6-di-trifluoromethyl-phenylimino)-

[Produce]

Each component is mixed well and the mixture is granulated according to conventional methods. It is compressed to make 430 mg of tablets containing 15 mg of active ingredient.

[Preparation Example 2: Gelatin Capsule]

The ingredients of the capsule are as follows.

2- (2,6-di-trifluoromethylphenyl-imino)-

[Produce]

Each component is mixed well and 200 mg of this mixture is filled into gelatin capsules of appropriate size. The active ingredient content per capsule is 25 mg.

Preparation Example 3: Injection Solution

This solution consists of the following composition:

2- (2,6-di-trifluoromethyl-phenylimino)-

Imidazolidine 1.5 parts

0.2 part sodium salt of ethylenediamine-tetra acetic acid

100.0 parts of distilled water

[Produce]

The active ingredient and the sodium salt of ethylenediamine tetraacetic acid are dissolved in a sufficient amount of water and filled with water to the desired degree. The solution is filtered to remove suspended particles and aseptically filled into 2 ml ampoules. Sterilize and seal this ampoule. The active ingredient content of each ampoule is 20 mg.

Claims (1)

And reacting the compound of formula (II) with ethylenediamine and optionally converting the compound produced above into its physiologically toxic acid addition salt thereof, the 2,6-disubstituted 2-phenyl of formula (I) Method for preparing imino-imidazolidine and its physiologically poisonous acid addition salts

Z is 2-ethyl-6-methylphenyl, 2,6-difluorophenyl, 2-chloro-6-fluorophenyl, 2,6-dimethoxyphenyl, 2,6-dihydroxyphenyl, 2 , 6-ditrifluoromethoxyphenyl, 2-bromo-6-methylphenyl, 2-bromo-6-chlorophenyl, 2-chloro-6-trifluoro-methylphenyl or 2-fluoro-6-trifluoro Chloromethylphenyl and X and Y represent the same or different halogen atoms (preferably chlorine), sulfhydryl, alkylthio, alkoxy, hydroxy, amino or nitroamino groups wherein the alkyl group represents 1 to 4 carbon atoms It contains.