DE1470319C3 - Benzimidazole derivatives, processes for their preparation and pharmaceuticals containing them - Google Patents

Description

NH-CO-CH, -N

(IX)

have anti-inflammatory effects, but without the undesirable side effects mentioned above. In addition, individual representatives of the new group of compounds also show analgesic effectiveness.

The invention relates to benzimidazole derivatives of the general formula I

wherein X, R ₁ and R ₂ as well as m have the meaning given in claim 1, subjecting the ring closure reaction to the benzimidazole or that one
g) O-phenylenediamine of the formula Χ

NH,

NH,

(X)

those under a) to e) for N-substituted o-phenylenediamines Subjects specified reactions and then the hydrogen atom in the 1-position of the imidazole ring through the rest

- (CH ₂ ) ,,,

—X

From the series of benzimidazoles are already compounds with spasmolytic and antiallergic Effectiveness known. These derivatives are in the 2-position Basically substituted and contain, for example, an aryl or aralkyl radical in the 1-position (cf. DT-PS 90 644).

Furthermore, benzimidazoles which are basicly substituted in the 1-position have been described which are analgesic and have anti-inflammatory effects. However, these compounds have undesirable side effects on; thus, when applied in large quantities, they result in a severe decrease in the respiratory rate that produce an anti-inflammatory effect (see F. Gross and H. T u r r i a η, Exp.XIII 402 [1957]).

It has now been found that a number of benzimidazole derivatives which have basic substituents in the 2-position and which have certain aryl or aralkyl groups in the 1-position, surprisingly strongly in which X is a hydrogen or chlorine atom and m is 0.1 or 2 , R _{1 is} a hydrogen atom and R _{2 is} a hydroxyethoxyethyl group or R ₁ and R ₂ together with the nitrogen atom form the group

—N N-Y

where Y represents a hydrogen atom, a methyl group or a hydroxyethyl group, as well as their salts with physiologically acceptable acids.

The benzimidazole derivatives according to the invention are prepared in a manner known per se by man

a) substituted o-phenylenediamines of the general formula II

substituted, in which X and m have the meaning given above, and the products obtained are optionally converted into their salts with physiologically acceptable acids.

10. Medicament consisting of a compound according to claim 1 and pharmaceutically usual Auxiliary and carrier materials.

(CH ₂ ) ,,,

NH

NH,

• X

(II)

in which X and m have the meaning given above, with aliphatic α-halogen or -hydroxyacetic acids of the general formula III

HOOC-CH ₉

(III)

wherein Z represents a halogen atom or the hydroxyl group, or their reactive, functional ones modified acid derivatives are ring-closed and then obtained 2- (halomethyl) -benzimidazoles with amines of the general formula IV

HN

(IV)

in which R ₁ and R _{2 have} the meaning given above or 2- (hydroxymethyl) -benzimidazoles obtained are converted with thionyl chloride into the 2- (halomethyl) -benzimidazoles and these are reacted with the amines of the general formula IV or that one

b) substituted ο-phenylenediamines of the general Formula II with the salts of imino ethers of the general formula V

NH

Il

RO-C-CH ₂ halo

(V)

where R is an alkyl group, ring-closed condensed, followed by the 2- (halomethyl) -benzimidazoles be reacted with amines of the general formula IV or that one

c) substituted o-phenylenediamines of the general formula II with an aminoacetic acid of the general formula Formula VI

have processing, subject to the ring closure reaction to give benzimidazole or that one

g) o-phenylenediamine of the formula X

NH,

NH,

(X)

subjected to the reactions given under a) to e) for N-substituted o-phenylenediamines and then the hydrogen atom in the 1-position of the imidazole ring through the remainder

HOOC-CH ₇ -N

(VI)

- (CH ₂ ) ,,,

wherein R ₁ and R _{2 have} the meaning given above, or their reactive, functionally modified acid derivatives are ring-closed condensed or that one

d) substituted o-phenylenediamines of the general formula II with the salts of basic substituted imino ethers of the general formula VII

NH R ₁

Il /

RO-C-CH ₂ -N

(VII)

wherein R, R ₁ and R _{2 have} the meaning given above, ring-closing condensation or that one

e) substituted o-phenylenediamines of the general formula II with an aldehyde of the general formula VIII

OHC - CH ₂ - Q (VIII)

in which Q is a hydroxyl group, a halogen atom or the group

substituted-t, in which X and m have the meaning given above.

To implement the o-phenylenediamines with acetic acids, which are in the «position by a basic group, a halogen atom or a hydroxyl group can, as already mentioned, instead of the Acetic acids also related to the corresponding esters with lower alcohols or the acid halides will.

The following Table I gives an overview of compounds in which the anti-inflammatory effect is particularly pronounced. To test the new compounds for their anti-inflammatory activity, the inhibition of kaolin edema is determined in rats by oral administration. The therapeutic index, formed from the LD ₅₀ and the ED _50, serves as a basis for comparison. The standard and reference substance is 3,5-dioxole, 2-diphenyl-4-n-butyl-pyrazolidine (III), which is known for its anti-inflammatory properties.

—N

N-Y

denotes, where Y has the meaning given above condensed in the presence of an oxidizing agent and then, if Q stands for a halogen atom or the hydroxyl group, proceed according to a) or that one

f) substituted o-phenylenediamines of the general formula IX

(IX)

wherein X, R ₁ , R ₂ and m have the abovementioned meaning

Table I _,,. ,. .

Therapeutic index

3,5-Dioxo-1,2-diphenyl-4-ri-butylpyrazolidine (III) (reference substance) 4

1- (4-chlorobenzyl) -2- [1- (2-hydroxyethyl) -4-piperazinyl] methylbenzimidazole 6th

1- [2- (4-chlorophenyl) ethyl] -2- [1- (2-hydroxyethyl) -4-piperazinyl] -
methylbenzimidazole 4

As can be seen from the table, the compounds mentioned have the same or a stronger one anti-inflammatory effects like III.

Many of the benzimidazole derivatives mentioned have analgesic effects. The pain reliever The effect of the compounds is in the copper plate test on the mouse with the known analgesic 1 - phenyl - 2,3 - dimethyl - 4 - dimethylamino - 5 - pyrazolone (I) for toxicity and efficacy been compared.

Table II shows the relative effectiveness of two compounds according to the invention in comparison to I = I listed. One of them showed a clearly superior effect compared to the comparison substance on.

Table II

ED ₅ ,,

relative

effectiveness

Table III

LD ₅₀ p.o. ED ₅₀ 385 (mg / kg) i.v. p.o. l- [2- (4-chlorophenyl) ethyl] - 113 10 2- [1 - (2-hydroxyethyl) -4-piper- 540 azinyl] methylbenzimidazole 1 - (4-chlorobenzyl) -2- [4-piper- 103 375 15th azinyl] methylbenzimidazole 1 -Benzyl-2- [1 -methyl-4-piper- 87 643 8th azinyl] methylbenzimidazole l- (4-chlorobenzyl) -2- [1-methyl- 116 20th 4-piperazinyl] -methylbenz- 455 imidazole 1 -Benzyl-2- [1 - (2-hydroxy- 81 5 ethyl) -4-piperazinyl] methyl 625 benzimidazole l- (4-chlorobenzyl) - 113 7th 2- [1 - (2-hydroxyethyl) -4-piper- 625 azinyl] methylbenzimidazole 270 II 140 25th III 160 320

IO

1- (4-chlorobenzyl) -2- [2- (2-hydroxy-3,5

ethoxy) -ethyl-amino] -methylbenzimide-

1- (4-chlorophenyl) -2- [l-methyl- I

4-piperazinyl] methylbenzimidazole

Another group of benzimidazole derivatives shows an antiallergic effect similar to that of e.g. des 1 - ρ - chlorobenzyl - 2 - pyrrolidylmethyl - benzimidazoles (II) and 3,5 - dioxo - 1,2 - diphenyl - 4n - butylpyrazolidine (III) are in some cases considerably superior.

In the case of allergic phenomena, tissue mast cells are destroyed and thus released of histamine, serotonin, plasma kinins and ferments with proteolytic, esterolytic and fibrinolytic activity.

This process can be experimentally by intracutaneous injection of Compound 48/80, a Condensation product from p-methoxyphenylethyl-N-methylamine with formaldehyde, imitate. In this so-called Evans-Blue-Spreadihg test you can the influence of released substances can be read off.

Table III shows the values which were obtained with the aid of the Evans Blue test.

35

40

45

55

The preparation of a salt of the benzimidazole derivatives is not described in all cases. All However, free bases dissolve in the equivalent amount of hydrochloric acid to form a solution of the monochlorohydrate. The new benzimidazole derivatives are in this form or as a salt of other pharmacologically harmless acids used.

The following examples illustrate the preparation of the compounds according to the invention.

example 1

1-p-chlorobenzyl-2-chloromethylbenzimidazole chlorohydrate is converted into the free base by trituration with water and sodium bicarbonate. The damp Product is recrystallized from dilute methanol with coal cleaning. Yield 67g, melting point 99 to 103 ° C (compound A).

45 g of compound A is dissolved in 240 ml of absolute benzene. Under cooling with ice water is a solution of 37.2 g of N-methylpiperazine in 40 ml of absolute benzene was added dropwise. The reaction mixture is washed neutral for 2 days. After drying over potassium carbonate, the solution is in vacuo at evaporated to a maximum of 30 ° C.

The raw base is recrystallized from petroleum ether. There are 40 g of colorless crystals of 1- (4-chlorobenzyl) -2- [l-methyl-4-piperazinyl] methylbenzimide azole, melting point 99 to 100.5 ° C. The base is used to prepare the monochlorohydrate dissolved in the 5-fold amount of acetone and mixed with the calculated amount of 1 η-hydrochloric acid. The solvent is driven off in vacuo, the residue is boiled with acetone, whereupon it crystallizes. The yield is almost quantitative (melting point 225 to 226 ° C).

Example 2

A solution of 43 g is added to a solution of 40 g of compound A in 300 ml of absolute benzene Given N- (2-hydroxyethyl) piperazine in 50 ml of absolute benzene. Occasional immersion of the Flask in ice water, the temperature in the flask is kept at 25 ° C. After standing overnight it will the reaction solution was refluxed for 2 hours. After cooling, it becomes neutral with water washed and extracted with 1 η hydrochloric acid. The combined hydrochloric acid extracts are twice with Washed with ether, decolorized with charcoal and made alkaline with sodium carbonate. The one who fails Precipitate is extracted with methylene chloride, the extract is dried with sodium sulfate and then evaporated at a maximum of 40 ° C. The residue is recrystallized from benzene with coal cleaning. Yield: 40 g of colorless crystals of 1- (4-chlorobenzyl) -2-1- [2 - (hydroxyethyl) -4-piperazinyl] -methylbenzimidazole (Melting point 144 to 145 ° C).

Example 3

4.76 g of compound A are dissolved in 16.5 ml of absolute ethanol. This solution is added dropwise within half an hour with exclusion of moisture to a solution of 3.8 g of β-amino-β'-hydroxydiethyl ether in 6.5 ml of absolute alcohol. The mixture is then ^{refluxed 2 ×} / ₂ hours. The alcohol is then distilled off in vacuo under nitrogen. The residue is dissolved in methylene chloride and washed neutral with water. After drying over sodium sulfate, the methylene chloride is evaporated off in vacuo. 6 g of viscous, brown oil remain. It is converted into the monohydrochloride with the calculated amount of 1η hydrochloric acid and recrystallized from a methanol-ether mixture. This gives 3.5 g of l- (4-chlorobenzyl) -2 - [2 - (2 - hydroxyethoxy) - ethylamino] - methylbenzimidazole of melting point 199-201 ⁰ C.

609 620/8

Example 4 Example 7

75.8 g of p-chlorobenzyl cyanide are dissolved in 700 ml of methanol saturated with ammonia and hydrogenated with 3 g of Raney nickel at an initial pressure of 110atü and a maximum temperature of 70.degree. After the usual work-up, 56.4 g of 4-chlorophenylethylamine (K ₁₄ 124 to 129 ^° C.) are isolated.

49 g of this compound are mixed with 49.5 g of o-chloronitrobenzene and 47.1 g of powdered anhydrous potassium carbonate for 3 hours in an oil bath at an internal temperature held at 150 to 160 ° C. After cooling, the melt is in chloroform and water solved. The chloroform solution is washed with dilute hydrochloric acid and then with water and dried and evaporated. The residue is recrystallized from methanol. 69 g of 1- (4-chlorophenylethylamino) -2-nitrobenzene are thus obtained receive.

The catalytic hydrogenation of this substance with Raney nickel in methanol gives 63 g of 1- (4-chlorophenylethylamino) -2-aminobenzoI, a viscous oil.

The oil is in 500 ml of abs. Dissolved chloroform and added to a suspension of 38 g of chloroacetic acid iminomethyl ether chlorohydrate in 200 ml of chloroform. The mixture is stirred at room temperature for half an hour, then at 40 ° C. for 2 hours. Water is then stirred into the batch and the mixture is neutralized with sodium hydrogen carbonate. The chloroform phase is separated, washed with water and dried over sodium sulfate. After evaporation of the chloroform in vacuo, 70 g of 1- (4-chlorophenylethyl) -2-chloromethylbenzimidazole (melting point 104 to 107 ° C.) remain. The reaction of 15.2 g of this compound with 15.6 g of N- (2-hydroxyethyl) piperazine according to Example 3 gives 16 g of the compound 1 - [2- (4-chlorophenyl) ethyl] -2- [1- (2-hydroxyethyl) -4-piperazinyl] -methylbenzimidazole (melting point 123 to 124 ⁰ C).

Example 5

40

A mixture of 12.8 g formylpiperazine, 6.4 g sodium carbonate and 150 ml 95% ethanol 33.1 g of compound A were added in the cold with stirring. After the addition, the reaction mixture becomes initially heated slightly, later refluxed for 2 hours. After cooling down, the Solution filtered, then evaporated in vacuo. The oily residue is mixed with 32 ml of hydrochloric acid of density 1.19 and 150 ml of water are added and the mixture is heated on the steam bath for 10 hours. Then in a vacuum around most of the hydrochloric acid is distilled off. The residue is stirred into water. With diluted Sodium hydroxide is used to fill the base. It is taken up in methylene chloride, the methylene chloride extract dried over potassium carbonate and evaporated. The residue, 1- (4-chlorobenzyl) -2- (4-piperazinyl) -methylbenzimidazole, melts, recrystallized from ethyl acetate, at 140 to 142 ° C, yield 20 g.

Example 6

By conversion of 1- [2 * (4-chlorophenyl) ethyl] -2-chloromethylbenzimidazole (See Example 5) with N-methyl-piperazine analogously to Example 11 is obtained 1 - [2 - (4 - chlorophenyl) - ethyl] - 2 - [1 - (methyl) - 4 - piperazinyl] methylbenzimidazole from melting point 122 to 123 ° C (recrystallized from cyclohexane) in one 90% yield.

A mixture of 11.9g «- (4-chlorophenyl) ethylamine, 1.3 g of o-chloronitrobenzene and 9.8 g of potassium carbonate are added to 170 bis in a metal bath for 5 hours Heated to 180 ° C. After cooling, the reaction mixture is distributed between ether and water. The ethereal phase is washed first with dilute hydrochloric acid, then with water until the wash water reacts neutrally. Then the ethereal solution is dried and evaporated. The residue crystallizes when rubbed with isopropanol. The yield is 14 g of N - (2 - nitrophenyl) -N - [(/ - (4-chlorophenyl) ethyl] amine (yellow crystals with a melting point of 56 to 57 ° C).

The nitro group of this compound is reduced according to Example 4.

The N - (2-aminophenyl) - N - [«- (4-chlorophenyl) ethyl] amine is isolated as an oil and soon with chloroacetic acid iminomethyl ether hydrochloride for 1 - [«- (4 - chlorophenyl) - ethyl] - 2 - chloromethylbenzimidazole reacted. This connection was not obtained crystalline. It was used as a crude product in the final stage.

18 g of the chloromethyl compound are dissolved in 100 ml of anhydrous chloroform. With exclusion of moisture, a solution of 18.4 g of N- (2-hydroxyethyl) piperazine in 100 ml of absolute chloroform is added dropwise to this solution. After standing overnight, the reaction mixture is refluxed for 3 hours and, after cooling, washed neutral with water. The neutral solution is extracted with hydrochloric acid. The hydrochloric acid extract is treated with charcoal and extracted with ether. Then it is made strongly alkaline with sodium hydroxide solution and the precipitated free base is extracted with methylene chloride. The free base, the l- [2- (4-chlorophenyl) ethyl] -2- [l- (2-hydroxyethyl) -4-piperazinyl] -methylbenzimidazol (m.p. 149-150 ⁰ C), after from this solution isolated using the usual methods. The yield is 9 g.

Example 8

10 g of N- (4-chlorobenzyl) -o-phenylenediamine are mixed with 4.6 g of glycolic acid. The flask is placed under a water jet vacuum. In the oil bath is slowly heated to 100 ^0C. In this case, the water is split off. The temperature is slowly increased to 135 ° C. and maintained for 1 hour. After cooling, the residue is dissolved in hot alcohol and so much water is added that no precipitate has yet formed. Then soda solution is added and cooled with ice water. The 1- (4-chlorobenzyl) -2-hydroxymethylbenzimidazole precipitates. It is filtered off with suction, washed with water and recrystallized while still moist from dilute alcohol with the addition of charcoal (melting point 131 to 132 ° C.). The yield is 10 g.

40 ml of thionyl chloride are added to these 10 g while cooling with ice water. Then will Boiled under reflux for 4 hours. The excess thionyl chloride is then removed under a nitrogen atmosphere distilled off in vacuo. The residue is dried over potassium hydroxide in a vacuum desiccator. It is then, as described in Example 1, converted into the free base with the aid of sodium bicarbonate. 10 g of compound A are obtained (melting point 100 to 102 ° C.). As in the

Example 2, by reaction with N- (2-hydroxyethyl) - piperazine in the 1 - transfer methylbenzimidazole (melting point 145 ⁰ C) - (4 - chlorobenzyl) -2 - [1 - (2 - hydroxyethyl) - 4 - piperazinyl] .

Example 9

1- (4-chlorobenzyl) -2-hydroxymethylbenzimidazole is obtained from N- (4-chlorobenzyl) -o-phenylenediamine and hydroxyacetic acid iminomethyl ether hydrochloride in a 58% yield analogously to Example 4. According to Example 8, it is converted into the chloromethyl compound. Reaction with N-methylpiperazine according to Example 6 gives l- (4-chlorobenzyl) - 2 - (1 - methyl - 4 - piperazinyl) - methyl lbenzimidazol in a yield of 73% of theory (melting point 99 to 100 ⁰ C).

Example 10

Using the method of Example 3, 32 g of 1-benzyl-2-chloromethylbenzimidazole with 57.9 g are obtained ß-Amino-ß'-hydroxydiethyl ether implemented. It will 30 g of an oily base are obtained, which are taken up in the equivalent amount of 0.5 η-hydrochloric acid. the After coal cleaning, the solution is evaporated in vacuo. The crystalline residue becomes twice recrystallized from methanol / ether. 7.7 g of 1 - benzyl - 2 - [2 - (2 - hydroxyethoxy) - ethylamino] methylbenzimidazole hydrochloride are thus obtained obtained from melting point 174 to 175 ° C.

Example 11

30 g of N-methyl-N'-cyanomethylpiperazine are in 12.6 ml of absolute ethanol and 200 ml of absolute ether dissolved. The solution is cooled to 0 ° C. at at this temperature, dry hydrogen chloride is passed in with stirring until it is saturated. Already at the beginning of the gas introduction, the crystallization of a colorless substance begins. After standing overnight the substance is filtered off with suction, washed with anhydrous ether and dried over potassium hydroxide. Yield: 47 g of N-methylpiperazinoacetic acid iminoether dichlorohydrate. (Decomposition point 94 ° C.)

To a solution of 5 g of N- (p-chlorobenzyl) -o-phenylenediamine in 20 ml of absolute chloroform while stirring and cooling with ice water in portions a suspension of 5.75 g of N-methylpiperazinoacetic acid iminomethyl ether dichlorohydrate added in 100 ml of absolute chloroform. The reaction mixture is left to stand with stirring overnight and then refluxed for 5 hours. The mixture is then evaporated in vacuo. The residue is dissolved in dilute hydrochloric acid and the aqueous solution is washed with ether, treated with charcoal and made alkaline with sodium carbonate. The deposited precipitate is in Methylene chloride added. The methylene chloride solution is dried over sodium carbonate and evaporated in vacuo. The residue is recrystallized from petroleum ether. This makes 2 g colorless Crystals of 1 - (4 - chlorobenzyl) - 2 - [(I - methy 1-4-piperazinyl) methyl] benzimidazole obtained from melting point 99 to lOrC.

Example 12

A solution is added to a solution of 20 g of o-phenylenediamine and 70 g of copper acetate in 600 ml of water of 18 g of chloroacetaldehyde hemihydrate in 250 ml of water was added. The reaction mixture is 20 minutes warmed up on the steam bath. It is then cooled and the precipitate which has separated out is filtered off with suction. the Precipitate is taken up in 300 ml of 6N hydrochloric acid in the warm and into the hot solution Hydrogen sulfide initiated. The precipitated copper sulfide is sucked off hot and the filtrate with Sodium hydrogen carbonate neutralized. The precipitated 2-chloromethylbenzimidazole is filtered off with suction, washed with water and dried. Yield:

12.5 g, melting point 147-152 ° C.

To a solution of 12.5 g of 2-chloromethylbenzimidazole in 170 ml of absolute ethanol, a solution of 18 g of N-methylpiperazine in 25 ml of absolute Ethanol was added while stirring and cooling with ice water. The reaction mixture is left overnight left to stand at room temperature and then refluxed for 2 hours. cooked. After that it is concentrated to dryness in vacuo. The residue is triturated with water and the resulting Mixture extracted five times with methylene chloride. The combined methylene chloride extracts are dried over potassium carbonate. The solvent is then distilled off in vacuo. the crystalline residue is taken up in a mixture of equal parts of ethyl acetate and methanol, and the solution is shaken with charcoal and filtered off. The solution is concentrated in vacuo, until strong crystallization sets in. After cooling with ice, the crystals are filtered off with suction. So 7 g 2 - [(1 - Methyl - 4 - piperazinyl) - methyl] - benzimidazole obtained (melting point 176 to 178 ° C). From the Mother liquor can be concentrated again to obtain a further 3 g with a melting point of 173 to 176 ° C will.

4.6g2 - [(1-methyl - 4 - piperazinyl) - methyl] - benzimidazole are in 120 ml of a mixture of 3 parts dissolved absolute toluene and a part of absolute dimethylformamide. 0.7 g are added to this solution Sodium hydride was added in the form of a 50% mineral oil suspension. The mixture is 1 hour stirred at 60 ° C. Then 3.8 g of benzyl chloride dissolved in 10 ml of toluene are added dropwise with stirring. added. After the addition is complete, the reaction mixture is stirred for a further 3 hours 80 ° C heated. It is cooled with ice and 20 ml of water are added dropwise with stirring. the organic phase is separated off, washed with water, dried and evaporated. The residue recrystallized from ethyl acetate with coal cleaning.

1.2 g of 1-benzyl-2 - [(1-methyl-4-piperazinyl) methyl] benzimidazole are thus obtained obtained from melting point 121 to 122 ° C.

Example 13

10 g of o-nitroaniline are dissolved in 100 ml of toluene while warm. To the warm solution will be under Stirring 8.18 g of chloroacetyl chloride added dropwise. After the addition has ended, the reaction mixture is 3 hours refluxed. Then the solution is evaporated in vacuo. The residue is made from ethanol recrystallized. Yield 12 g, 1-chloroacetylamino-2-nitro-benzene, Melting point 87 to 89 ° C.

14 g of l-chloroacetylamino-2-nitrobenzene are in 130 ml of absolute benzene dissolved. A solution of 20 g of N- / f-hydroxyethyl piperazine is added to this solution while cooling with ice added in 10 ml of absolute benzene. After standing overnight, the reaction mixture is refluxed for 3 hours. Subsequent

It is then washed neutral with water. the Crystals which precipitate are filtered off with suction, and the benzene phase, washed neutral, is evaporated. The residue is combined with the initially precipitated crystals. 19 g of l - [(l- / i-hydroxyethyl - 4 - piperazinyl) - acetyl] - amino - 2 - nitrobenzene. After recrystallization from ethyl acetate 16 g of a pure product with a melting point of 111 to 113 ° C. remain.

25 g of 1 - [(1 - /? - HydroxyäthyI-4-piperazinyl) -acetyl] -amino-2-nitrobenzoI are hydrogenated in 300 ml of methanol with Raney nickel as a catalyst at room temperature and a pressure of 100 atm. After the usual work-up, 22 g of 1 - [(I - β - hydroxyethyl-4 - piperazinyl) - acetyl] - amino - 2 - aminobenzene, a compound which is sensitive to atmospheric oxygen and has a melting point of 138 to 140 ^° C., are obtained.

8 g of this compound are dissolved in 150 ml of methanol and 3 drops of piperidine are added to the solution. A solution of 2.9 ml of benzaldehyde in 10 ml of methanol is added dropwise with stirring. After standing over Nacfit, the solution is evaporated. The dark oil that remains is treated with hexane and ether and crystallized in this way. The crystals are dissolved in benzene, a benzene-insoluble amorphous residue is filtered off. The filtrate is treated with charcoal and evaporated. The residue is worked through with hexane. When rubbed with ether it crystallizes. 5 g of yellow crystals are obtained, after drying over phosphorus pentoxide and paraffin, the melting point is 83 to 86 ^° C. It is the l - [(l - /? - hydroxyethyl-4-piperazinyl) acetyl] amino 2-benzalaminobenzene. This compound is hydrogenated as a 10% solution in dioxane with Raney nickel as a catalyst at a temperature of 60 to 80 ° C. and a hydrogen pressure of 100 atm. The 1 - [(I - ß - hydroxyethyl) - 4 - piperazinyl) - acetyl] amino-2-benzylaminobenzene obtained after conventional work-up does not crystallize. The yield is practically quantitative.

5 g of this compound are dissolved in 50 ml of glacial acetic acid. 3 g of sodium acetate are added to the solution added. The reaction mixture is refluxed for 3 hours. Then the solution is in Poured water, made the mixture alkaline with sodium hydroxide solution and extracted with methylene chloride. The combined methylene chloride extracts are washed with a little water and dried over sodium sulfate and evaporated. The residue is recrystallized from benzene ίο. 2 g of l-benzyl-2- [l- (2-hydroxyethyl) -4-piperazinyl] methylbenzimidazole are thus obtained obtained from melting point 138 to 139 ° C.

Example 14

15 g of o-chloronitrobenzene, 6 g of 4-chloroaniline and 15 g of sodium acetate are mixed well. The mixture is heated 10 hours at 200 to 21O ⁰ C. It is then cooled, mixed with dilute hydrochloric acid and freed from excess chloronitrobenzene by steam distillation. The distillation residue is cooled and the brown crystals which have precipitated out are filtered off with suction. They are recrystallized from ethanol and water.

Yield: 6 g of 4'-chloro-2-nitrodiphenylamine.

25 g of this nitro compound are dissolved in 100 ml of dioxane and 1 g of Raney nickel as a catalyst hydrogenated at room temperature and an initial pressure of 115 atmospheres. After the usual work-up 22 g of 4'-chloro-2-aminodiphenylamine are obtained.

22 g of the amino compound are converted into 1- (4-chlorophenyl) -2-chloromethylbenzimidazole (melting point 119 to 121 ^° C.) by condensation with chloroacetic acid iminomethyl ether hydrochloride. Yield: 26 g.

The chloromethyl compound is reacted according to Example 2 with N-methylpiperazine. You get 1 - (4 - chlorophenyl) - 2 - [1 - methyl - 4 - piperazine] methylbenzimidazole (melting point 167 to 169 ° C, from ethyl acetate).

Claims (9)

Patent claims: 1. Benzimidazole derivatives of the general formula I ) " (CH ₂ ) ,,, —N N-Y NH, HOOC - CH, - Z (III) IO (D where X is a hydrogen or chlorine atom and m is 0, 1 or 2, R _{1 is} a hydrogen atom and R _{2 is} a hydroxyethoxyethyl group or R ₁ and R ₂ together with the nitrogen atom are the grouping 20th where Y represents a hydrogen atom, a methyl group or a hydroxyethyl group, and their salts with physiologically acceptable acids. 2. 1 - (4 - chlorobenzene) - 2 - [1 - methyl - 4 - piperazinyO-methylbenzimidazole. 3. 1 - (4 - Chlorbencyi) - 2 - [1 - (2 - hydroxyethyl) -4-piperazinyl] methylbenzimidazole. 4. 1 - (4-chlorobenzene) - 2 - [2 - (2 - hydroxyethoxy) ethyl-amino] methylbenzimidazole. 5. 1- [2- (4-chlorophenyl) ethyl] -2- [1- (2-hydroxyethyl) -4-piperazinyl] methylbenzimidazole. 6. 1 - (4-Chlorobenzyl) -2- (4-piperazinyl) -methylbenzimidazole. 7. 1 - (4-ChlorophenyI) -2- [1 -methyl-4-piperazinylj-methylbenzimidazole. 8. 1 - Benzyl-2- [1 - (2-hydroxyethyl) -4-piperazinylj-methylbenzimidazole. 9. A method for the preparation of compounds according to claim 1, characterized in that one in a manner known per se a) substituted o-phenylenediamines of the general formula II (H) 55 wherein X and m have the meaning given above, with aliphatic α-halogen or u-hydroxy acetic acids of the general formula III wherein Z represents a halogen atom or the hydroxyl group, or their reactive, functional ones modified acid derivatives ring-closed condensed and then obtained 2- (Halogcnmethyl) -benzimidazoles with amines of the general formula IV HN (IV) in which R ₁ and R _{2 have} the meaning given above or 2- (hydroxymethyl) -benzimidazoles obtained are converted with thionyl chloride into the 2- (halomethyl) -benzimidazoles and these are reacted with the amines of the general formula IV or that one b) substituted o-phenylenediamines of the general Formula II with salts of imino ethers of the general formula V NH Il RO-C-CH ₂ -halogen (V) where R is an alkyl group, ring-closed condensed, followed by the 2- (halomethyl) -benzimidazoles be reacted with amines of the general formula IV or that one c) substituted o-phenyldiamines of the general formula II with an aminoacetic acid of the general formula Formula VI HOOC-CH ₇ -N (VI) wherein R ₁ and R _{2 have} the meaning given above, or 'their reactive, functionally modified acid derivatives are ring-closed condensed or that one d) substituted o-phenylenediamines of the general formula II with the salts of basic substituted Imino ethers of the general formula VII NH R ₁ Il / RO-C-CH ₂ -N R ₂ (VII) in which R, R ₁ and R _{2 have} the meaning given above, ring-closed condensation or that e) substituted 0-phenylenediamines of the general formula II with an aldehyde of the general formula VIII OHC-CH ₂ -Q (VIII) in which Q is a hydroxyl group, a halogen atom or the group —N N-Y means, where Y has the meaning given above, in the presence of an oxidizing agent con- condensed and then, if Q is a halogen atom or sees the hydroxyl group, proceeding according to a) or that one f) substituted o-phenyl diamine of the general formula IX (CH ₂ ) ,,,
NH