DD232697A5 - PROCESS FOR THE PREPARATION OF BENZIMIDAZOLENE - Google Patents

Abstract

The invention relates to novel benzimidazoles of the general formula I in which R1 is a hydroxy, alkoxy, phenylalkoxy, cyanoalkoxy, alkylsulfenyl, alkylsulfinyl, alkylsulfonyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, alkylsulfoximino, alkenyloxy or R 2 is a hydrogen atom or an alkoxy group and R 4 is a hydrogen or halogen atom, a cyano, nitro, amino, carboxy , Alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, aminocarbonylamino, alkylaminocarbonylamino or dialkylaminocarbonylamino groups, their tautomers and their acid addition salts, which have valuable pharmacological properties, in particular an effect on the blood pressure and the contractility of the cardiac muscle. The new compounds can be prepared by methods known for analogous compounds.

Description

- A

Berlin, August 14, 85 AP C 07 D / 271 449/2 64 614 11

Process for the preparation of benzimidazoles

Field of application of the invention

The invention relates to a process for the preparation of benzimidazoles having valuable pharmacological properties, in particular having a positive inotropic, antihypertensive and / or antithrombotic effect.

The compounds prepared according to the invention are used as medicaments, in particular for the treatment of cardiac insufficiencies of different origins.

Characteristic of the known technical solutions

Z «B, mebendazole £ (5-benzoyl-1H-benzimidazol-2-yl) -carbaminsäuremethylester_7 or thiabendazole £ 2- (4-thiazolyl) benzimidazole with anthelmintisehen properties are already known, -1H-benzimidazol_7.

Object of the invention

The aim of the invention is to provide novel compounds with valuable pharmacological properties, in particular with positive inotropic, antihypertensive and / or antithrombotic effects, which are suitable for the treatment of heart failure of different origin.

Explanation of the essence of the invention

The invention has for its object to find compounds with the desired properties and processes for their preparation ·

- ·, -7 - O O

According to the invention, new benzimidazoles of the general formula

(D

whose tautomers and their acid addition salts, in particular their physiologically tolerated acid addition salts with inorganic or organic acids, which have valuable pharmacological properties, in particular an effect on the blood pressure and on the contractility of the heart muscle, and medicaments containing these compounds.

In the above general formula I means

R _{1 represents} a hydroxy, alkoxy, phenylalkoxy, cyanoalkoxy, alkylsulfenyl, alkylsulfinyl, alkylsulfonyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, alkylsulfoximino, alkenyloxy or alkynyloxy group,

R _{2 is} a hydrogen atom, a hydroxy, alkoxy, phenylalkoxy, amino, alkylamino or dialkylamino group,

R, a hydrogen atom or an alkoxy group and

R is a hydrogen or halogen atom, a cyano, nitro, amino, carboxy, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, aminocarbonylamino, alkylaminocarbonylamino or dialkylaminocarbonylamino group, wherein the alkyl part has in each case 1 to 3 carbon atoms and the alkenyl or alkynyl part may each contain from 3 to 5 carbon atoms.

For example, the meanings mentioned in the "definition of the radicals R 1 to R" are as follows

R, the meaning of the hydroxy, methoxy, ethoxy, n-propoxy, benzyloxy, 1-phenylethoxy, 2-phenylethoxy, 3-phenylpropoxy, methylsulfenyl, ethylsulfenyl, isopropylsulfenyl, methylsulfinyl, Ethylsulfinyl, n-propylsulfinyl, methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl, cyanomethoxy, 2-cyanoethoxy, 3-cyano-propoxy, aminosulfonyl, methylaminosulfonyl, ethylaminosulfonyl, n -propylaminosulfonyl, dimethylaminosulfonyl , Diethylaminosulfonyl, diisopropylaminosulfonyl, N-methylethylaminosulfonyl, methylsulfoximino, ethylsulfoximino, n-propylsulfoximino, allyloxy, but-2-enyloxy, pent-2-enyloxy, propargyloxy, but-2-ynyloxy or pent-2-ynyloxy group,

R _{2 represents} that of the hydrogen atom, the methoxy, ethoxy, n-propoxy, isopropoxy, benzyloxy, 1-phenylethoxy, 2-phenylethoxy, 3-phenylpropoxy, amino, methylamino, ethylamino, Isopropylamino, dimethylamines, diethylamino, di-n-propylamino, diisopropylamino, N-methylethylamino, N-methylisopropylamino or N-ethyl-n-propylamino group,

for R-, the hydrogen atom, the methoxy, ethoxy, n-propoxy or isopropoxy and

for R ₄ those of the hydrogen, fluorine, chlorine or bromine atom, the cyano, nitro, amino, carboxy, methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, aminocarbonyl, methylaminocarbonyl, ethylaminocarbonyl, n Propylaminocarbonyl, dimethylaminocarbonyl, diethylaminocarbonyl, diisopropylaminocarbonyl, aminocarbonylamino, methylaminocarbonylamino, ethylaminocarbonylamino, n-propylaminocarbonylamino, dimethylaminocarbonylamino, diethylaminocarbonylamino, di-n-propylaminocarbonylamino or N-methylethylaminocarbonylamino groups.

Preferred compounds of the above general formula I are those in which

R, and R. are as defined above, R ~ except for the hydrogen atom has the meanings mentioned for R-, and

R _{3 represents} a hydrogen atom,

in particular those compounds in which R _{1 is} in the 4-position and R _{2 is} in the 2-position

R ₄ with the exception of the hydrogen atom at the beginning of R ₄

has the meanings mentioned.

Particularly preferred compounds are the compounds of the general formula

in the

R, a hydroxy, benzyloxy, allyloxy, propargyloxy, alkylsulfenyl, alkylsulfinyl, alkylsulfonyl, alkylsulfoximino or aminosulfonyl group,

K ~ an alkoxy group and

R _{4 is} a fluorine, chlorine or bromine atom, a cyano, carboxy, aminocarbonyl, alkoxycarbonyl, nitro or amino group, wherein the alkyl moiety may each contain 1 or 2 carbon atoms, their tautomers and their acid addition salts, in particular their physiological compatible acid addition salts with inorganic or organic acids.

According to the invention, the new compounds are obtained by the following processes:

a) cyclization of a compound of the general formula optionally prepared in the reaction mixture

- X

¹ NH-Y

(ID

in the

R ₄ as defined above,

one of the radicals X or Y is a hydrogen atom and the other of the two radicals X and Y or both radicals X and Y is a group of the formula

- C

R.

represent in the

R, to R _{3 are} as defined above, Z, and Z ~ t may be the same or different, optionally substituted amino groups or optionally substituted by lower alkyl groups hydroxy or mercapto groups or

Z, and Z-, together represent an oxygen or sulfur atom, an imino group optionally substituted by an alkyl group having 1 to 3 carbon atoms, an alkylenedioxy or alkylene dithio group each having 2 or 3 carbon atoms.

The cyclization is conveniently carried out in a solvent or solvent mixture such as ethanol, isopropanol, glacial acetic acid, benzene, chlorobenzene, toluene, xylene, glycol, glycol monomethyl ether, diethylene glycol dimethyl ether, sulfolane, dimethylformamide, tetralin or in excess of the acylating agent used to prepare the compound of general formula II For example, in the corresponding nitrile, anhydride, acid halide, ester, amide or methoiodide, for example at temperatures between 0 and 250 ⁰ C, but preferably at the boiling temperature of the reaction mixture, optionally in the presence of a condensing agent such as phosphorus oxychloride, thionyl chloride, sulfuryl chloride, sulfuric acid, p Toluenesulfonic acid, hydrochloric acid, phosphoric acid, polyphosphoric acid, acetic anhydride or optionally also in the presence of a base such as potassium or potassium tert.butylat performed. However, the cyclization can also be carried out without a solvent and / or condensing agent.

b) For the preparation of compounds of general formula I in which R represents an alkylsulfinyl or alkylsulfonyl group:

Oxidation of a compound of the general formula

(III)

in the

R_ to R. are as defined above and R, 'an alkylsulfenyl or

Alkylsulfinyl group each having 1 to 3 carbon atoms in the alkyl moiety.

The oxidation is preferably carried out in a solvent or solvent mixture, for example in water, water / pyridine, acetone, glacial acetic acid, dilute sulfuric acid or trifluoroacetic acid, depending on the oxidant used expediently at temperatures between -80 and 100 ⁰ C.

For the preparation of an alkylsulfinyl compound of general formula I, the oxidation is conveniently carried out with one equivalent of the oxidizing agent used, for example with hydrogen peroxide in glacial acetic acid, trifluoroacetic acid or formic acid at 0 to 20 ⁰ C or in acetone at 0 to 60 ⁰ C, with a peracid such as performic acid in glacial acetic acid or trifluoroacetic acid at 0 ois 50 ⁰ C or with m-chloroperbenzoic acid in methylene chloride or chloroform at -20 to 60 ⁰ C, with sodium metaperiodate in aqueous methanol or ethanol at -15 to 25 ^0C, with bromine in glacial acetic acid or aqueous acetic acid, with N-bromo-succinimide in ethanol, with tert.butyl-hypochlorite in methanol at -80 to -30 ⁰ C, with iodobenzodichloride in aqueous pyridine at 0 to 5O ⁰ C,

with nitric acid in glacial acetic acid at 0 to 20 ⁰ C / with chromic acid in glacial acetic acid or in acetone at 0 to 20 ⁰ C and with sulfuryl chloride in methylene chloride at -70 ⁰ C, the resulting thioether-chloro complex is suitably hydrolyzed with aqueous ethanol.

For the preparation of an alkylsulfonyl compound of the general formula I, the oxidation is advantageously carried out with one or two or more equivalents of the oxidizing agent used, for example with hydrogen peroxide in glacial acetic acid, trifluoroacetic acid or in formic acid at 20 to 100 ⁰ C or in acetone at 0 to 6O ⁰ C, with a peracid such as performic acid or m-chloroperbenzoic acid in glacial acetic acid, trifluoroacetic acid, methylene chloride or chloroform at temperatures between 0 and 60 ⁰ C, with nitric acid in glacial acetic acid at 0 to 20 ⁰ C, with chromic acid or potassium permanganate in glacial acetic acid, water / sulfuric acid or in acetone at 0 to 20 ^° C.

c) For the preparation of compounds of the general formula I in which R 1 represents an alkoxy, phenylalkoxy, cyanoalkoxy, alkylsulfenyl, alkenyloxy or alkynyloxy group:

Reaction of a compound of the general formula

in the

R4 as defined above,

U represents a hydroxy or mercapto group, R2 'has a hydroxy group or the meanings mentioned for R2, and

ι 15 β λ λ -j

Ro 'has a hydroxy group or the meanings mentioned for R 3, with a halide of the general

formula

WR ₅ , (V)

in the

R _{5 is} an alkyl, phenylalkyl, cyanoalkyl, alkenyl or alkynyl group, where the alkyl moiety may contain in each case 1 to 3 carbon atoms and the alkenyl or alkynyl moiety each contain 3 to 5 carbon atoms, and W denotes a nucleophilic leaving group such as a chlorine, Represent bromine or iodine atom.

The reaction is conveniently carried out in a solvent such as tetrahydrofuran, dioxane, dimethylformamide, sulfolane, dimethylsulfoxide or ethylene glycol dimethyl ether, preferably in the presence of an acid-binding agent such as potassium carbonate, potassium tert-butylate or sodium hydride at temperatures between 0 and 10O ⁰ C, but preferably at temperatures between 20 and 50 ^° C.

d) For the preparation of compounds of general formula I in which R. represents an alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl or dialkylaminocarbonyl group:

Reaction of a benzimidazole of the general formula

HOOC

(VI)

in the

R ₁ to R are as defined above, or their corresponding

if appropriate, in the reaction mixture produced reactive derivative with a compound of the general formula

HR ₆ , (VII)

in the

Rg represents an alkoxy, amino, alkylamino or dialkylamino group, it being possible for the alkyl part to contain in each case 1 to 3 carbon atoms, or with an N-activated amine of the general formula VII optionally formed in the reaction mixture, if a carboxylic acid of the general formula VI is used ,

The process thus relates to the acylation of a compound of general formula VII with a carboxylic acid of general formula VI in the presence of an acid activating or dehydrating agent or with their functional derivatives or

the reaction of a carboxylic acid of the general formula VI with an amine of the general formula VII in the presence of an amino group-activating agent or with its reactive derivatives.

Examples of suitable functional derivatives of a carboxylic acid of the formula VI which are optionally prepared in the reaction mixture are their alkyl, aryl or aralkyl esters or thioesters, such as the methyl, ethyl, phenyl or benzyl esters, their imidazolides, their acid halides, such as the acid chloride or bromide , their anhydrides, their mixed anhydrides with aliphatic or aromatic carboxylic, sulfonic, SuIfin- or sulfonic acids or carbonic acid esters ^ - eg acetic acid, propionic acid, p-toluenesulfonic acid or O-ethyl-carbonic acid, their O-triphenylphosphonium complexes, their N-acyl-oxyimides, their azides or nitriles or the corresponding amino-thiocarboxylic acid derivatives, and as optionally prepared in the reaction mixture Derivatives of an amine of the general formula VI whose phosphazoderivate into consideration.

Suitable acid-activating and / or dehydrating agents are, for example, a Chlorameisensäureester such as ethyl chloroformate, thionyl chloride, phosphorus trichloride, phosphorus pentoxide, N, N ¹ -dicyclohexylcarbodiimide, N, N ¹ -carbonyldiimidazole, N, N ¹ -Thionyldiimidazol, boron trifluoride etherate or triphenylphosphine / carbon tetrachloride into consideration,

The reaction is conveniently carried out in a solvent such as methylene chloride, chloroform, carbon tetrachloride, ether, tetrahydrofuran, dioxane, benzene, toluene, acetonitrile or dimethylformamide, optionally in the presence of an inorganic base such as sodium carbonate or a tertiary organic base such as triethylamine or pyridine, which are also solvents can be used, and optionally in the presence of an acid-activating agent at temperatures between -25 and 250 ⁰ C, but preferably at temperatures between -10 ⁰ C and the boiling temperature of the solvent used, carried out. In this case, a functional derivative of a compound of general formula VI or VII, which may have been formed in the reaction mixture, need not be isolated, and the reaction may also be carried out without a solvent. Furthermore, water formed during the reaction can be separated off by azeotropic distillation, for example by heating with toluene on a water separator, or by adding a desiccant such as magnesium sulfate or molecular sieve.

e) For the preparation of compounds of the general formula I in which R · is an alkylsulfoximino group:

Reaction of a sulfoxide of the general formula

in the

R_ to R. are as defined above and R _{7 represents} an alkyl group having 1 to 3 carbon atoms, with hydrazoic acid optionally formed in the reaction mixture.

The reaction is conveniently carried out in a solvent or solvent mixture such as methylene chloride, dimethylformamide or tetrahydrofuran at temperatures between 0 and 4O ⁰ C, preferably at temperatures between 10 and 35 ° C. The reaction is particularly advantageously carried out with an alkali azide, for example sodium azide, and polyphosphoric acid as solvent.

f) For the preparation of compounds of general formula I in which R represents an alkylsulfoximirto group:

Reaction of a sulfoxide of the general formula

SOR "

(Viii)

R ₂

in the

R ₂ to R are as defined above and R _{7 represents} an alkyl group having 1 to 3 carbon atoms, with a compound of the general formula

H ₂ N - O - W - Rg, (IX)

in the

W represents a carbonyl or sulfonyl group and Rg represents an o-position disubstituted aryl group such as a 2,4,6-trimethylphenyl or 2,4,6-triisopropylphenyl group.

The reaction is conveniently carried out in a solvent or solvent mixture such as methylene chloride, chloroform, dimethylformamide, tetrahydrofuran or dioxane at temperatures between 0 and 5O ⁰ C, but preferably at temperatures between 5 and 40 ⁰ C, and optionally in the presence of a catalytic amount of an acid such as p Toluenesulfonic acid performed. However, the reaction is particularly advantageously carried out in such a way that a compound of general formula IX is used without their previous isolation or is prepared in the reaction mixture.

If, in accordance with the invention, a compound of the general formula I in which R represents an alkoxycarbonyl, cyano, aminocarbonyl, alkylaminocarbonyl or dialkylaminocarbonyl group can be synthesized by means of hydroxylation in a corresponding compound of the general formula I in which R. the carboxyl group represents, be transferred and / or

a compound of the general formula I in which R. represents an aminocarbony group, this can be converted by means of dehydration into a corresponding compound of the general formula I, in which R. represents the cyano group, and / or

a compound of general formula I in which R _{4 represents} a nitro group, it may be converted by reduction into a corresponding compound of general formula I in which R _{a represents} an amino group, and / or

a compound of the general formula I in which R _{4 represents} an amino group, this can be converted by means of carbamoylation into a corresponding compound of the general formula I in which R represents an aminocarbonylamino, alkylaminocarbonylamino or dialkylaminocarbonylamino group, and / or

a compound of general formula I, in which R, and / or R- represent a benzyloxy group, this can be converted by debenzylation into a corresponding compound of general formula I in which R, and / or R _{2 represent} a hydroxy group.

The subsequent hydrolysis is conveniently carried out either in the presence of an acid such as hydrochloric acid, sulfuric acid, phosphoric acid or trichloroacetic acid or in the presence of a base such as sodium hydroxide or potassium hydroxide in a suitable solvent such as water, water / methanol, ethanol, water / ethanol, water / isopropanol or water / Dioxane at temperatures between -10 and 12O ⁰ C, for example at temperatures between room temperature and the boiling temperature of the reaction mixture, carried out, but the partial hydrolysis is preferably carried out with concentrated sulfuric acid.

The subsequent dehydration is carried out with a dehydrating agent such as phosphorus pentoxide, phosphorus oxychloride, sulfuric acid or p-toluenesulfonyl chloride optionally in a solvent such as methylene chloride or pyridine at temperatures between 0 and 100 ⁰ C, preferably at temperatures between 20 and 80 ⁰ C.

The subsequent reduction of the nitro group is preferably carried out in a solvent such as water, water / ethanol, methanol, glacial acetic acid, ethyl acetate or dimethylformamide conveniently with hydrogen in the presence of a hydrogenation catalyst such as Raney nickel, platinum or palladium / carbon, with metals such as iron, tin or zinc , sulfate in the presence of an acid, with salts such as iron (II), tin (II) chloride, sodium sulfide, sodium hydrosulfide · or sodium dithionite, or with hydrazine in the presence of Raney nickel at temperatures between 0 and 5O ⁰ C, but preferably at room temperature, carried out.

The subsequent carbamoylation is carried out in an inert solvent such as water, methylene chloride, tetrahydrofuran or dioxane with an appropriate isocyanate such as methyl isocyanate or potassium isocyanate in the presence of an acid such as acetic acid or with a corresponding carbamoyl chloride such as dimethylaminocarbonyl chloride at temperatures between and 50 ⁰ C.

Subsequent debenzylation is conveniently carried out in a solvent such as methanol, ethanol, ethyl acetate or glacial acetic acid by means of catalytically-promoted hydrogen, e.g. with hydrogen in the presence of platinum or palladium / carbon, at temperatures between 0 and 75 ° C, but preferably at room temperature, and carried out at a hydrogen pressure of 1-5 bar.

Furthermore, the compounds of the general formula I obtained can, if desired, subsequently be converted into their physiologically tolerated acid addition salts with inorganic or organic acids. Examples of suitable acids are hydrochloric, hydrobromic, sulfuric, phosphoric, fumaric, succinic, tartaric, citric, lactic, maleic and methanesulfonic acids.

The compounds of the general formulas II to IX used as starting materials are known in the literature in some cases or are obtained by processes known from the literature.

Thus, for example, the compounds of general formula II used as starting materials by acylation of a corresponding o-diamino compound and the compounds of general formulas III, IV, VI and VIII by subsequent condensation with a corresponding benzoic acid derivative and optionally subsequent oxidation (see EP-AO. 022495).

As already mentioned, the new compounds of general formula I, their IH tautomers and their physiologically tolerated acid addition salts have a long duration of action superior pharmacological properties, in particular a hypotensive, positive inotropic and / or antithrombotic effect.

For example, the compounds were

A = 2- (2-methoxy-4-ethylsulfonyl-phenyl) -5-cyano-benzimidazole and

B = 2- (2-methoxy-4-propargyloxy-phenyl) -5-cyanobenzimidazole was examined for its biological properties as follows:

Determination of the blood pressure effect and the positive inotropic effect on the anesthetized cat

The studies were performed in cats that were anesthetized with pentobarbital sodium (40 mg / kg ip). The animals breathed spontaneously. Arterial blood pressure was measured in the abdominal aorta with a Statham pressure transducer (P 23 Dc). To measure the positive inotropic effect, the pressure in the left ventricle was measured with a catheter tip manometer (Millar PC-350 A). From this, the contractility _parameter ^ Ρ / ^^ _{3Χ was obtained} by means of an analog differentiator. The substances to be tested were injected into a femoral vein. The solvent used was polydiol 200. Each substance was tested on at least 3 cats.

The following table contains the mean values found:

substance Dose mg / kg i.v # Increase in blood pressure reduction • P 'max in mm Hg in % A A A 0.2 0.6 2.0 51 - 29 / -23 96 - 36 / -37 79 - 49 / -48 PQ PQ PQ 0.2 0.6 2.0 33 - 40 / -27 48 - 48 / -37 85 - 57 / -33

The new compounds are well contracted, so no herpes toxicity or circulatory damage could be observed in the investigation of substances A and B.

Owing to their pharmacological properties, the compounds of the general formula I which are produced according to the invention and their physiologically tolerated acid addition salts are suitable for treating cardiac insufficiencies of different origins, since they increase the contraction force of the heart and facilitate the emptying of the heart by lowering the blood pressure. The new compounds can be used for this purpose as well as their physiologically acceptable acid addition salts, optionally in combination with other active substances, into the usual pharmaceutical application forms such as tablets, dragees, powders, suppositories, suspensions, ampoules or drops. The single dose is in this case 1 to 4 times daily 0.3 to 2.2 mg / kg body weight, but preferably 0.7 to 1.5 mg / kg body weight.

embodiment

The following examples are intended to explain the invention in more detail:

- 17 Example 1

2- (2-methoxy-4-methylmercapto · phenyl) -5-methoxycarbonyl-benz imidazole

23.9 g of 4-methoxycarbonyl-l, 2-phenylenediamine dihydrochloride and 19.8 g of 2-methoxy-4-methylmercapto-benzoic acid are heated with 700 ml of phosphorus oxychloride for 2.5 hours at reflux. Subsequently, the excess phosphorus oxychloride is distilled off in vacuo, the crystalline residue is stirred with ice water, treated with concentrated ammonia to alkaline reaction and the crystals filtered off with suction. It is crystallized from 70% ethyl alcohol and dried at 70 ⁰ C.

Melting point: 206-208 ⁰ C, yield: 23.0 g (70% of theory).

The following compounds are obtained analogously:

2- (2-methoxy-4-ethylmercapto-phenyl) -5-methoxycarbonyl-benzimidazole

2- (2-Ethoxy-4-n-propylmercapto-phenyl) -5-methoxycarbonyl-benzimidazole

2- (2-methoxy-4-methylmercapto-phenyl) -5-propoxycarbonyl-benzimidazole

Example 2

2- (2-methoxy-4-methylmercapto-phenyl) -5-carboxy-benzimidazole

10.2 g of 2- (2-methoxy-4-methylmercapto-phenyl) -5-methoxycarbonyl-benzimidazole are refluxed for 2 hours in 300 ml of 2N sodium hydroxide solution. Then it will be

filtered hot over diatomaceous earth and acidified with 2N hydrochloric acid. It is suctioned off, washed with water and dried at 70 ⁰ C.

Melting point: 308-310 ⁰ C (decomposition), yield: 8.6 g (88% of theory).

The following compounds are obtained analogously:

2- (2-methoxy-4-ethylmercapto-phenyl) -5-carboxy-benzimidazole

2- (2-ethoxy-4-n-propylmercapto-phenyl) -5-carboxy-benzimidazole

Example 3

2- (2-methoxy-4-methylmercapto-phenyl) -5-aminocarbonyl-benz imidazole

6.7 g of 2- (2-methoxy-4-methylmercapto-phenyl) -5-carboxy-benzimidazole, suspended in 120 ml of chloroform, are added dropwise at reflux with 25.4 g of thionyl chloride with vigorous evolution of gas. After 2 hours of heating, the mixture is cooled to room temperature and sucks off the acid chloride formed. The crude product is introduced into 100 ml of concentrated ammonia. The resulting acid amide is filtered off with suction, dissolved in boiling hot ethanol and precipitated with hot water. The crystals are filtered off with suction and dried at 80 ⁰ C.

Melting point: 138-142 ° C, yield: 4.5 g (67.4% of theory).

The following compounds are obtained analogously:

2- (2-methoxy-4-methylmercapto-phenyl) -5-methylaminocarbonylbenzimidazol

2- (methoxy) -methylmercapto-phenyl) -5-ethylaminocarbonylbenzimidazole

2- (2-methoxy-4-methylmercapto-phenyl) -5-dimethylaminocarbonyl-benzimidazole

2- ^ -methoxy-methylmercapto-phenyl) -5-di-n-propylaminocarbonylbenzimidazole

2- (2-Methoxy-4-ethylmercapto-phenyl) -5-aminocarbonylbenzimidazole

2- ^ -ethoxy-methylmercapto-phenyl) -5-methylaminocarbonylbenzimidazole

2- (2-Ethoxy-4-ethylmercapto-phenyl) -5-diethylaminocarbonylbenzimidazole

2- (2-methoxy-4-n-propylmercapto-phenyl) -S-aminocarbonyl-benzimidazole

Example 4

2- (2-Methoxy-4-methylmercapto-phenyl) -5-cyano-benzimidazole ·

3.5 g of 2-U-methoxy-methylmercapto-phenyl) -5-aminocarbonyl-benzimidazole are heated with 100 ml of phosphorus oxychloride for 2.5 hours at reflux and then distilled off the excess phosphorus oxychloride in vacuo. The residue is decomposed with ice / water, treated with concentrated ammonia to alkaline reaction and filtered with suction. The resulting crystals are dried at 70 ⁰ C. Melting point: 211-215 ° C, yield: 3.05 g (92.4% of theory).

The following compounds are obtained analogously: 2- (2-Methoxy-4-ethylmercapto-phenyl) -5-cyano-benzimidazole 2- (2-Methoxy-4-n-propylmercapto-phenyl) -5-cyano-benzimidazole 2- (2 -ethoxy-4-methylmercapto-phenyl) -5-cyano-benzimidazole

Example 5

2- (2-methoxy-4-methylsulfinyl-phenyl) -5-cyano-benzimidazole

2.0 g of 2- (2-methoxy-4-methylmercapto-phenyl) -5-cyano-benzimidazole are dissolved in 50 ml of glacial acetic acid and treated with 0.61 ml of hydrogen peroxide (399 mg / ml). After 14 hours, 50 ml of water and 3 ml of a 40% sodium bisulfite solution are added, then evaporated to dryness in vacuo. The residue is taken up with water, filtered off with suction and dried at 70 ⁰ C.

Melting point: 115-116 ⁰ C, yield: 1.79 g (84.9% of theory) The following compounds are obtained analogously: 2- (2-methoxy-4-ethylsulfinyl-phenyl) -5-cyano-2- benzimidazole (2-Methoxy-4-n-propylsulfinylphenyl) -5-cyanobenzimidazole 2- (2-Ethoxy-4-methylsulfinyl-phenyl) -5-cyano-benzimidazole

Example 6

2- (2-Methoxy-4-methylsulfonylphenyl) -5-cyano-benzimidazole 0.7 g of 2- (2-methoxy-4-methylmercapto-phenyl) -5-cyano-benzene

imidazole are dissolved in 10 ml of formic acid, treated with 0.51 ml of hydrogen peroxide (399 mg / ml) and allowed to stand for 4 hours. Then it is diluted with 40 ml of water, the precipitated crystals filtered off and dried at 60 ⁰ C. Melting point: 260-261 ⁰ C, yield: 0.71 g (91.5% of theory) .-

The following compounds are obtained analogously: 2- (2-Methoxy-4-ethylsulfonyl-phenyl) -5-cyano-benzimidazole 2- (2-Methoxy-4-n-propylsulfonyl-phenyl) -5-cyano-benzimidazole 2- (2 -ethoxy-4-methylsulfonyl-phenyl) -5-cyano-benzimidazole

Example 7

2- (2-methoxy-4-methylsulfoximino-phenyl) -5-cyano-benzimidazole

0.623 g of 2- (2-methoxy-4-methylsulfinyl-phenyl) -5-cyano-benzimidazole, dissolved in 5 ml of dimethylformamide, are treated with 1.43 g of O-mesitylene-sulfonyl-acethydroxamic acid ethyl ester and 1.71 g of p-toluenesulfonic acid. After 20 hours, add 10 ml of water and add concentrated ammonia until alkaline. The crystallizing substance is recrystallized from ethanol

 Melting point: 262-263 ° C (dec.), Yield: 0.33 g (50.6% of theory).

The following compound is obtained analogously:

2- (2-methoxy-4-ethylsulfoximino-phenyl) -5-cyano-benzimidazole

Example 8 2- (2-Methoxy-4-methylsulfinylphenyl) -5-carbamidobenzimidazole

Prepared analogously to Example 5 from 2- (2-methoxy-4-methylmercapto-phenyl) -5-carbamido-benzimidazole and hydrogen peroxide in glacial acetic acid.

Melting point: 175-178 ° C, yield: 53.5% of theory.

The following compounds are obtained analogously:

2- (2-methoxy-4-ethylsulfinyl-phenyl) -5-carbamido-benzimidazole

2- (2-methoxy-4-n-propylsulfinyl-phenyl) -5-carbamido-benzimidazole

2- (2-ethoxy-4-methylsulfinyl-phenyl) -5-carbamido-benzimidazole

Example 9

2- (2-Methoxy-4-methylsulfonyl-phenyl) -5-carbamido- benzimidazole

Prepared analogously to Example 6 from 2- (2-methoxy-4-methylmercapto-phenyl) -5-carbamido-benzimidazole and hydrogen peroxide in formic acid

Melting point: 278-280 ⁰ C, yield: 41.6% of theory.

The following compounds are obtained analogously:

2- (2-methoxy-4-ethylsulfonyl-phenyl) -5-carbamido-benzimidazole

2- (2-methoxy-4-n-propylsulphonyl-phenyl) -5-carbamidobenzimidazole

2- (2-ethoxy-4-methylsulfonyl-phenyl) -5-carbamido-benzimidazole

Example 10

2- (2-methoxy-4-methylsulfoximino-phenyl) -5-carbamido-benz imidazole

Prepared analogously to Example 7 from 2- (2-methoxy-4-methylsulfinyl-phenyl) -S-carbamido-benzimidazole and O-mesitylene-acethydroxamic acid ethyl ester

 Melting point: 260-262 ° C, yield: 41.4% of theory.

The following compounds are obtained analogously:

2- (2-Methoxy-4-ethylsulfoximino-phenyl) -5-carbamido-benzimidazole

2- (2-methoxy-4-n-propylsulfoximino-phenyl) -5-carbamido-benzimidazole

2- (2-ethoxy-4-methylsulfoximino-phenyl) -5-carbamido-benzimidazole

Example 11

2- (2-methoxy-4-benzyloxy-phenyl) -5-fluoro-benzimidazole

Prepared analogously to Example 1 from 2-amino-4-fluoroaniline and 2-methoxy-4-benzyloxy-benzoic acid in boiling phosphorus oxychloride.

Melting point: 190-191 ⁰ C,

Yield: 59.2% of theory.

The following compounds are obtained analogously: 2- (2-methoxy-4-benzyloxy-phenyl) -5-chloro-benzimidazole 2- (2-methoxy-4-benzyloxy-phenyl) -5-bromo-benzimidazole

Example 12

2- (2-methoxy-4-hydroxy-phenyl) -5-fluoro-benzimidazole

2.1 g of 2- (2-methoxy-4-benzyloxy-phenyl) -5-fluoro-benzimidazole are dissolved in 100 ml of ethanol with 0.2 g of palladium / carbon (10%) at 2O ⁰ C and a hydrogen pressure of 4 hydrogenated bar catalytically. Thereafter, the catalyst is filtered off, the clear solution is evaporated and the residue brought to crystallization by trituration with ether. Melting point: 291-293 ° C, yield: 87.7% of theory.

Example 13

2- (2-methoxy-4-cyanomethoxy-phenyl) -5-fluoro-benzimidazole

1.22 g of 2- (2-methoxy-4-hydroxy-phenyl) -5-fluoro-benzimidazole are dissolved in 10 ml of dimethylsulfoxide, treated with 0.65 g of anhydrous potassium carbonate and then 0.37 g of chloroacetonitrile, dissolved in 3 ml Dimethyl sulfoxide, added dropwise at 20 ⁰ C within 35 minutes with stirring. The mixture is stirred for 14 hours, carries the reaction mixture in 30 ml of ice water and 2n acetic acid to p "= 5. The precipitated product is by heating to 70 ⁰ C crystalline. It is suctioned off, washed with water and the substance is dried at 70 ⁰ C. For purification, the crude product is chromatographed on Er'ne silica gel column with a mixture of methylene chloride / ethyl acetate = 5: 1

Melting point: 185-190 ⁰ C, yield: 0.68 g (48.7% of theory).

The following compounds are obtained analogously:

2- (2-Methoxy-4-cyanomethylthio-phenyl) -5-fluoro-benzimidazole 2- (2-Methoxy-4-allyloxyphenyl) -5-fluoro-benzimidazole 2- (2-Ethoxy-4-cyanomethoxy-phenyl ) -5-fluoro-benzimidazole 2- (2-ethoxy-4-allylthio-phenyl) -5-chloro-benzimidazole 2- (2-methoxy-4-cyanomethoxy-phenyl) -5-bromo-benzimidazole 2- (2- methoxy-4-buten-2-yloxy-phenyl) -5-fluoro-benzimidazole

Example 14

2- (2-methoxy-4-propargyloxy-phenyl) -5-nitro-benzimidazole

Prepared analogously to Example 1 from 2-amino-4-nitro-aniline and 2-methoxy-4-propargyloxy-benzoic acid in boiling phosphorus oxychloride.

Melting point: 243-245 ⁰ C, yield: 83.1% of theory.

The following compounds are obtained analogously:

2- (2-Methoxy-4-butyn-2-yloxy-phenyl) -5-nitrobenzimidazole 2- (2-ethoxy-4-propargyloxy-phenyl) -5-nitrobenzimidazole

Example 15

2- (2-methoxy-propargyloxy-phenyl) -5- aminobenzimidazole 1.8 g of 2- (2-methoxy-4-propargyloxyphenyl) -5-nitro-benzimido-

azole are suspended in 50 ml of glacial acetic acid, heated to 90 ⁰ C and treated within 15 minutes with a solution of 9.4 g of sodium dithionite in 50 ml of water. The resulting light brown solution is evaporated on a rotary evaporator in vacuo. The residue is stirred with 50 ml of water, mixed with sodium carbonate until the alkaline reaction and extracted 3 times with a chloroform-methanol mixture = 4: 1. The entire extract is dried over magnesium sulfate, evaporated and the foamy residue dried in a desiccator.

Yield: 0.40 g (4.4% of theory),

R _f value: 0.25 (silica gel, eluent: ethylene chloride / ethanol = 9: 1).

The following compounds are obtained analogously:

2- (2-methoxy-4-butyn-2-yloxy-phenyl) -5-amino-benzimidazole

2- (2-ethoxy-4-propargyloxy-phenyl) -5-amino-benzimidazole

Example 16

2- (2-methoxy-4-propargyloxy-phenyl) -5-methylaminocarbonyl amino-benzimidazo!

0.36 g of 2- (2-methoxy-4-propargyloxy-phenyl) -5-amino-benzimidazole are dissolved in 5 ml of tetrahydrofuran, treated with 0.14 g of methyl isocyanate and heated at 60 ⁰ C for 2 hours. Thereafter, it is evaporated in vacuo. The residue is purified by column chromatography on silica gel with ethylene chloride / ethanol = 10: 1

Melting point: 203-204 ⁰ C, yield: 0.34 g (78.9% represents theory).

- 27 The following compounds are obtained analogously:

2- (2-methoxy-4-butyn-2-yloxy-phenyl) -5-methylaminocarbonylamino-benzimidazole

2- (2-Ethoxy-4-propargyloxyphenyl) -5-ethylaminocarbonylaminobenzimidazole

2- (2-ethoxy-4-propargyloxy-phenyl) -5-ethylaminocarbonylamino-benzimidazole

Example 17

2- (2-methoxy-4-propargyloxy-phenyl) -5-methoxycarbonyl-benz imidazole

Prepared analogously to Example 1 from 3,4-diamino-benzoic acid methyl ester dihydrochloride and 2-methoxy-4-propargyloxybenzoic acid boiling phosphorus oxychloride. Melting point: 116-120 ⁰ C, yield: 59.5% of theory.

The following compound is obtained analogously:

2- (2-ethoxy-4-propargyloxy-phenyl) -5-methoxycarbonyl-benzimidazole

Example 18

2- (2-methoxy-4-propargyloxy-phenyl) -5-carboxy-benzimidazole

Prepared analogously to Example 2 from 2- (2-methoxy-4-propargyloxy-phenyl) -5-methoxycarbonyl-benzimidazole and 2N sodium hydroxide. lye.

Melting point: 235-24O ⁰ C,

Yield: 92.8% of theory.

The following compounds are obtained analogously:

2- (2-ethoxy-4-propargyloxy-phenyl) -5-carboxy-benzimidazole

2- (2-Methoxy-4-allyloxy-phenyl) -5-carboxy-benzimidazole

Example 19

2- (2-methoxy-4-propargyloxy-phenyl) -5-arainocarbonyl-benz imidazole

Prepared according to Example 3 from 2- (2-methoxy-4-propargyloxy-phenyl) -S-carboxy-benzimidazole and thionyl chloride and subsequent reaction of the resulting 2- (2-methoxy-4-propargyloxy-phenyl) -5-chlorocarbonyl-benzimidazole with concentrated ammonia. The crude product is purified by column chromatography on silica gel with Et'hylenchlorid / ethanol = 9: 1

Melting point: 150-152 ⁰ C, yield: 35.0% of theory.

The following compounds are obtained analogously:

2- (2-methoxy-4-propargyloxy-phenyl) -5-methylaminocarbonylbenzimidazol

2- (2-ethoxy-4-propargyloxy-phenyl) -5-aminocarbonyl-benzimidazole

2- (2-methoxy-4-allyloxy-phenyl) -5-aminocarbonyl-benzimidazole

? - (2-methoxy-4-allyloxy-phenyl) -5-n-propylamino-carbonylbenzimidazol

Example 20 2- (2-Methoxy-4-propargyloxy-phenyl) -S-cyano-benzimidazole

Prepared analogously to Example 1 from 2-amino-4-cyano-aniÜn and 2-methoxy-4-propargyloxy-benzoic acid in boiling Phosphoroxychlor id.

Melting point: 243-245 ⁰ C, yield: 85.0% of theory.

The following compound is obtained analogously:

2- (2-ethoxy-4-propargyloxy-phenyl) -5-cyano-benzimidazole

Example 21

2- (2-methoxy-4-aminosulfonyl-phenyl) -5-cyano-benzimidazole

a) 1.47 g of 2-nitro-4-cyano-aniline and 1.96 g of 2-methoxy-4-aminosulfonyl-benzoyl chloride are refluxed in 50 ml of dry chlorobenzene for 5 hours. Crystals of (2-methoxy-4-aminosulfonyl) -benz- (2-nitro-4-cyano) -anilide precipitate from the originally clear solution during this time. It is still sucked off, washed with a little cold chlorobenzene and then with ethyl acetate and dried at 6O ⁰ C.

Melting point: 270-274 ⁰ C,

Yield: 2.47 g (72.9% of theory).

b) 2.40 g of the substance obtained according to Example a) are slurried in 250 ml of glacial acetic acid, mixed with 20 g of iron powder and heated to boiling for 1.5 hours at reflux. The mixture is filtered from the iron residue, the glacial acetic acid is distilled off in vacuo and the residue is stirred with water. The precipitated crystals are sucked off and on a

Silica gel column with methylene chloride / ethyl acetate = 1: 1 chromatographed. White crystals of 2- (2-methoxy-4-aminosulfonyl-phenyl) -5-cyano-benzimidazole are obtained. Melting point: 284-286 ⁰ C, yield: 0.455 g (21.7% of theory).

The following compounds are obtained analogously:

2- (2-methoxy-4-methylaminosulphonyl-phenyl) -5-cyano-benzimidazole

2- (2-methoxy-4-dimethylaminosulfonyl-phenyl) -5-cyano-benzimidazole

2- (2-ethoxy-4-aminosulfonyl-phenyl) -5-cyano-benzimidazole

2- (2-ethoxy-4-methylaminosulphonyl-phenyl) -5-cyano-benzimidazole

2- (2-ethoxy-4-dimethylaminosulfonyl-phenyl) -5-cyano-benzimidazole

2- (2-methoxy-4-n-propylaminosulfonyl-phenyl) -5-cyano-benzimidazole

2- (2-met-hoxy-4-di-n-propylaminosulfonyl-phenyl) -5-cyanobenzimidazole

example

2- (2-Methoxy-4-aminosulfonyl-phenyl) -5-methoxycarbonyl- benzimidazo!

Prepared analogously to Example 1 from 2-methoxy-4-aminosulphate

Fonyl-benzoic acid and 3,4-diamino-benzoic acid methyl ester in boiling phosphorus oxychloride

 Melting point: 284-286 ° C, yield: 48.4% of theory.

The following compounds are obtained analogously:

2- (2-methoxy-4-methylaminosulphonyl-phenyl) -5-methoxycarbonylbenzimidazole

2- (2-methoxy-4-dimethylaminosulfonyl-phenyl) -5-methoxycarbonyl-benzimidazole

2- (2-ethoxy-4-di-n-propylaminosulfonyl-phenyl) -5-methoxycarbonyl-benzimidazole

Example 23 '

2- (2-methoxy-4-aminosulfonyl-phenyl) -5-carboxy-benzimidazole

Prepared analogously to Example 2 from 2- (2-methoxy-4-aminosulfonyl-phenyl) -5-methoxycarbonyl-benzimidazole with 2N sodium hydroxide solution.

Melting point: 321-323 ° C, yield: 61.5% of theory. _

The following compounds are obtained analogously:

2- (2-methoxy-4-methylaminosulphonyl-phenyl) -5-carboxy-benzimidazole

2- (2-methoxy-4-dimethylaminosulfonyl-phenyl) -5-carboxy-benzimidazole

- 32 Example 24

2- (2-methoxy-4-aminosulfonyl-phenyl) -5-aminocarbonyl-benz imidazole

Prepared analogously to Example 3 from 2- (2-methoxy-4-aminosulfonyl-phenyl) -5-carboxy-benzimidazole by reaction with thionyl chloride and then with concentrated ammonia. Melting point: 311-313 ° C, yield: 76.0% of theory.

The following compounds are obtained analogously:

2- (2-methoxy-4-aminosulfonyl-phenyl) -5-methylaminocarbonylbenzimidazol

2- (2-methoxy-4-methylaminosulphonyl-phenyl) -5-amino-carbonylbenzimidazol

2- (2-methoxy-4-dimethylaminosulfonyl-phenyl) -5-aminocarbonylbenzimidazol

2- (2-Methoxy-4-di-n-propylaminosulfonyl-phenyl) -5-aminocarbonylbenzimidazole

2- (2-Methoxy-4-aminosulfonylphenyl) -5-di-n-propylaminocarbonyl-benzimidazole

Example 25

2- (2-Methoxy-4-aminosulfonylphenyl) -5-aminocarbonyl-benzimidazole """""""'-""."""". - - -

0.657 g of 2- (2-methoxy-4-aminosulfonyl-phenyl) -5-cyano-benzimidazole are suspended in 2 ml of concentrated sulfuric acid.

registered way and left at 30 ⁰ C for 24 hours. Then it is decomposed with ice, sucks off the precipitated crystals and washed acid-free

Melting point: 311.5 to 313.5 ⁰ C, yield: 60.0% of theory.

- 34 Example A

Tablets to 100 mg of 2- (2-methoxy-4-propargyloxyphenyl) -5 · cyano-benzimidazole

Composition 1 tablet contains:

Active substance 100.0 mg

Lactose 50.0 mg

Polyvinylpyrrolidone 5.0 mg

Carboxymethylcellulose 19.0 mg

Magnesium stearate 1.0 mg

175.0 mg

Wet sieving: 1.5 mm

Drying: circulating air drying oven 50 ⁰ C Dry sieving: 1 mm

Mix the granules with the remaining excipients and compress the final mixture into tablets

 Tablet weight: 175 mg Stamp: 8 mm

Example B

Dragees to 50 mg of 2- (2-methoxy-4-propargyloxy-phenyl) -5-cyano-benzimidazole

Composition:

1 drag core contains:

Active substance ^: ^ MaFIs starch-ket tr.

Soluble starch carboxymethyl cellulose magnesium stearate

80.0 mg

50 , 0 mg 20 -0 .. mg 2 , 0 mg 7 , 0 mg 1 , 0 mg

Evenly moisten active ingredient and starch with aqueous solution of the soluble starch.

Wet sieving: 1.0 mm

Dry sieving: 1.0 mm,

Drying: 50 ⁰ C in a convection oven

Mix granules and remaining excipients and seeds

compress.

Core weight: 80 mg

Stamp: 6 mm

Buckling radius: 5 mm

The finished kernels are provided in the usual way with a sugar coating in the coating pan. Dragee weight: 120 mg

Example C

Suppositories to 75 mg of 8- (2-methoxy-4-propargyloxyphenyl) -5-cyano-benzimidazole

1 suppository contains:

Active substance 75.0 mg

Suppository mass (e.g., Witepsol H 19

and Witepsol W 45) 1 625.0 mg

1 700.0 mg

Production method:

The suppository mass is melted. At 38 ° C, the ground active substance in the enamel? homogeneously dispersed. It is cooled to 35 ^° C. and poured into precooled suppository molds.

Suppository weight: 1.7 g

- 36 Example D

Ampoules of 50 mg of 2- (2-methoxy-4-propargyloxy-phenyl) -5-cyano-benzimidazole

1 ampoule contains:

Active substance 50.0 mg

Ethoxylated hydroxystearic acid 750.0 mg

1,2-propylene glycol 1000.0 mg

Dest. Water ad 5.0 ml

Production method;

The active substance is dissolved in 1,2-propylene glycol and ethoxylated hydroxystearic acid, then made up to the stated volume with water and filtered sterile. Filling: in ampoules to 5 ml Sterilization: 20 minutes at 120 ⁰ C.

Example E

Drops to 100 mg 2- (2-methoxy-4 -propargyloxy-phenyl) -5- G cyano-benzimidazole G active substance 1.0 G Methyl p-oxybenzoate 0,035 G p-Oxybenzoesäurepropylester 0,015 G anisole 0.05 G menthol 0.06 G Sodium saccharine 1.0 _: g. , , , - glycerin 10.0 ml Ethanol. -.._. 4 0.0 Dest. Water ad 10 0 Γθ

- 37 manufacturing process;

The benzoic acid esters are dissolved in ethanol and then the anisole and menthol are added. Then the active substance, glycerol and sodium saccharin dissolved in the water is added. The solution is then filtered clear.

Claims (17)

Brfindungsanspruch  1. A process for the preparation of benzimidazoles of the general formula (D in the R .. a hydroxy, alkoxy, phenylalkoxy, cyanoalkoxy, alkylsulfenyl, alkylsulfinyl, alkylsulfonyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, alkylsulfoximino, alkenyloxy or alkynyloxy group, Rp represents a hydrogen atom, a hydroxy, alkoxy, phenylalkoxy, amino, alkylamino or dialkylamino group, R ^ is a hydrogen atom or an alkoxy group and R. is a hydrogen or halogen atom, a cyanogen, a nitro, amino, carboxy, alkoxycarbonyl, aminocarbonyl, alkylamino carbonyl, diallyl aminocarbonyl, aminocarbonylamino, Alkylaminocarbonylamino- or Dialkylaminocarbonylaminogruppe, wherein the alkyl moiety each 1 to 3 Carbon atoms and the alkenyl or alkynyl moiety may each contain from 3 to 5 carbon atoms, their tautomers and their acid addition salts, characterized in that 39 + 40 a) a compound of the general formula optionally prepared in the reaction mixture in the R. as defined in claim 1, one of the radicals X or Y is a hydrogen atom and the other of the two radicals X and Y or both radicals X and Y is a group of the formula .1 represent in the R- to R _{3 are} as defined in claim 1, Z-, and Z ₂ / which may be the same or different, optionally substituted amino groups or optionally substituted by lower alkyl groups hydroxy or mercapto groups or Z, and Z _2, together an oxygen or sulfur atom, an optionally substituted by an alkyl group having 1 to 3 carbon atoms, imino group, an alkylenedioxy or alkylenedithio group each represent 2 or 3 carbon atoms, is cyclised, or b) for the preparation of compounds of the general formula I in which R represents an alkylsulfinyl or alkylsulfonyl group, a compound of the general formula , (III) in the R ₂ to R, as defined in claim 1 and R · is an alkylsulfenyl or alkylsulfinyl group each having 1 to 3 carbon atoms in the alkyl moiety, is oxidized or c) for the preparation of compounds of the general formula I in which R represents an alkoxy, phenylalkoxy, cyanoalkoxy, alkylsulfenyl, alkenyloxy or alkynyloxy group, a compound of the general formula (IY) in the R _{4 is} as defined in claim 1, U is a hydroxy or mercapto group, R_ 'has a hydroxyl group or the meanings mentioned for R ₂ in claim 1 and R' has a hydroxyl group or the meanings mentioned for R_ in claim 1, with a Halide of the general formula W - in the R _{5 is} an alkyl, phenylalkyl, cyanoalkyl, alkenyl or alkynyl group, wherein the alkyl moiety may each contain 1 to 3 carbon atoms and the alkenyl or alkynyl moiety each have 3 to 5 carbon atoms, and W is a nucleophilic leaving group such as a chlorine -, bromine or iodine atom, is reacted or d) for the preparation of compounds of the general formula I in which R * represents an alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl or dialkylaminocarbonyl group, a benzimidazole of the general formula ^R 1 HOOC in the R to R _{3 are} as defined in claim 1, or their reactive derivative optionally prepared in the reaction mixture with a compound of the general formula HR ₆ , (VII) in the R ,. an alkoxy, amino, alkylamino or dialkylamino group, it being possible for the alkyl part to contain in each case 1 to 3 carbon atoms, or with an N-activated amine of the general formula VII optionally formed in the reaction mixture, if a carboxylic acid of the general formula VI is used, is implemented or e) for the preparation of compounds of the general formula I in which R represents an alkylsulfoximino group, a sulfoxide of the general formula ^R 4 in the R ₂ to R, as defined in claim 1 and R _{7 is} an alkyl group having 1 to 3 carbon atoms, is reacted with optionally formed in the reaction mixture of hydrazoic acid or f) for the preparation of compounds of the general formula I in which R- represents an alkylsulfoximino group, a sulfoxide of the general formula , (VIII) in the R ₂ to R are as defined in claim 1 and R _{7 is} an alkyl group having 1 brs 3 carbon atoms, with a compound of the general formula H ₂ N - 0 - W - R ₈ , (IX) in the W represents a carbonyl or sulfonyl group and R represents an o-position disubstituted aryl group such as a 2,4,6-trimethylphenyl or 2,4,6-triisopropylphenyl group and, if desired, subsequently a compound of the general formula I in which R _{4 is} an alkoxycarbonyl, cyano, aminocarbonyl, alkylaminocarbonyl or dialkylaminocarbonyl group, by means of hydroxylation, into a corresponding compound of the general formula I in which R. represents the carboxyl group , is transferred and / or a compound of the general formula I in which R.sup.1 is an aininocarbonyl group is converted by means of dehydration into a corresponding compound of the general formula I in which R. represents the cyano group, and / or a compound of general formula I wherein R.sup.1 is a hitro group is converted by reduction into a corresponding compound of general formula I in which R is an amino group and / or a resulting compound of the general formula I in which R. represents an amino group, is converted by carbamoylation in a corresponding compound of general formula I in which R ₄ represents an aminocarbonylamino, alkylaminocarbonylamino or dialkylamino carb onylaminogruppe and / or a compound of general formula I in which R- and / or R 1 represents a benzyloxy group is converted by debenzylation into a corresponding compound of general formula I in which R- and / or Rp represents a hydrosyl group, and / or a compound of the general formula I obtained is converted into its acid addition salt, in particular into its physiologically tolerated acid addition salt with an inorganic or organic acid, 2 · Process according to item 1, characterized in that benzimidazoles of general formula I are prepared, in which R and R are as defined in point 1, Rg with the exception of the hydrogen atom has the meanings mentioned for Rp, and R ~ represents a hydrogen atom, their tautomers and their acid addition salts · Method according to item 1, characterized in that benzimidazoles of the general formula I are prepared in which R ₁ to R _{3 are} as defined in point 2, R is in the 4-position and Rp is in the 2-position and R. with the exception of the hydrogen atom has the meanings mentioned for R ₄ in point 1, their tautomers and their acid addition salts. 4. The method according to item 1, characterized in that Benzimidazole the general Pormel (Ia) be prepared in the R _{1 is} a hydroxy, benzyloxy, allyloxy, propargyloxy, alkylsulfenyl, alkylsulfinyl, alkylsulfonyl, alkylsulfoximino or aminosulfonyl group, an alkoxy group and a Pluor-, chlorine od
Aminocarbonyl, alkoxycarbonyl, hitro or amino group , a pluor, chlorine or bromine atom, a cyano, carboxy, where the alkyl moiety may contain in each case 1 or 2 carbon atoms, their tautomers and their acid addition salts. 5. The method according to item 1, characterized in that 2- (2-methoxy-4-methylsulfonyl-phenyl) -5-cyano-benzimidazole, the tautomers and acid addition salts thereof are prepared. Process according to item 1, characterized in that 2- (2-Me-t-hoz: y-4-propargyloxy-phenyl) -5-cyano-benzimidazole, its tautomers and its acid addition salts are prepared 7. The method according to item 1, characterized in that the reaction is carried out in a solvent · 8. The method according to the points 1a and 1d, characterized in that the reaction is carried out in the presence of an acylating agent, a condensing agent or a base · 9 «method according to the points 1a, 1d, 7 and 8, characterized in that the reaction at temperatures between 0 and 250 ⁰ G, but preferably at the boiling temperature of the reaction mixture is carried out · 10. The method according to points 1b and 7, characterized in that the oxidation at temperatures between -80 and 100 ⁰ C, but preferably at temperatures between 0 and 60 ⁰ G, is performed. 11. The method according to points 1b, 7 and 10, characterized in that for the preparation of a sulfinyl compound of the general formula I, the oxidation is carried out with one equivalent of the used .Oxidationsmittels. 12. The method according to item 1c, characterized in that the reaction is carried out in the presence of an acid-binding agent · Process according to points 1c, 7 and 12, characterized in that the reaction is carried out at temperatures between 0 and 100 ^° C., but preferably at temperatures between 20 and 50 ^° C. Process according to points 1e and 7, characterized in that the reaction is carried out at temperatures between 0 and 40 ^° C., but preferably at temperatures between 10 and 35 ^° C. Process according to items 1f and 7, characterized in that the reaction is carried out in the presence of a catalytic amount of an acid. 16. Procedure under points 1f, 7 and 15? characterized in that the reaction at temperatures between 0 and 50 ⁰ C, but preferably at temperatures between 5 and 40 ⁰ C, is performed. 17 «A process for the preparation of a medicament, characterized in that a compound according to the items 1 to 6 or a physiologically acceptable acid addition salt thereof is incorporated into one or more inert carriers and / or diluents non-chemically.