NO845169L - ANALOGUE PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE BENZIMIDAZOLE DERIVATIVES - Google Patents

Description

This invention relates to a process for the production of new benzimidazole derivatives with the general formula

their tautomers and their acid addition salts, in particular their physiologically compatible acid addition salts with inorganic or organic acids, which exhibit valuable pharmacological properties, in particular an effect on blood pressure and on cardiac muscle contractility.

In the above general formula I means

R1 is a hydroxy, alkoxy, phenylalkoxy, cyanoalkoxy, alkylsulfenyl, alkylsulfinyl, alkylsulfonyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, alkylsulfoximino, alkenyloxy or alkynyloxy group,

1*2 a hydrogen atom, a hydroxy-, alkoxy-, phenyl-alkyl-,;amino-, alkylamino- or dialkylamino group,;Ro a hydrogen atom or an alkoxy group, and;a hydrogen or halogen atom, a cyan-, nitro-, amino-, carboxy, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, aminocarbonylamino, alkylaminocarbonylamino or dialkylaminocarbonylamino group, wherein the alkyl part in each case may contain 1 to 3 carbon atoms, and the alkenyl or alkynyl part in each case may contain 3 to 5 carbon atoms . ;Among the initially stated meanings for the residues;R-^ to R^, comes into consideration, for example; for the R^ meaning a 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-cyano- ethoxy-, 3-cyanopropoxy-, aminosulfonyl-, methylaminosulfonyl-, ethylaminosulfonyl-, n-propylaminosulfonyl-, dimethylaminosulfonyl-, ;diethylaminosulfonyl-, diisopropylaminosulfonyl-, N-methylethylaminosulfonyl-, methylsulfoximino-, ethylsulfoximino-, n-propylsulfoximino-, allyloxy-, but-2-enyloxy-, pent-2-enyloxy-, propargyloxy-, but-2-inyloxy- or pent-2-inyloxy group, for R~ meaning a hydrogen atom, a methoxy-, ethoxy-, n- propoxy-, isopropoxy-, benzyloxy-, 1-phenylethoxy-, 2-phenylethoxy-, 3-phenylpropoxy-, amino-, methylamino-, ethylamino-, isopropylamino-, di methylamino-, diethylamino-, di-n-propylamino-, diisopropylamino-, N-methyl-ethylamino-, N-methyl-isopropylamino- or N-ethyl-n-propylamino group, ; for R., the meaning of a hydrogen atom, a methoxy- , ethoxy-, n-propoxy or isopropoxy group and; for the R^ meaning a hydrogen, fluorine, chlorine, or bromine atom, a 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 group. Preferred compounds with the above general formula I are those where R^ and R^ are as indicated at the beginning, R2 has the meanings indicated for R2 at the beginning with the exception of a hydrogen atom, and R^ means a hydrogen atom, especially those compounds where R^ stands in 4-position and R2i 2-position, and R^ has the meanings indicated for R^ at the beginning with the exception of a hydrogen atom. Particularly preferred compounds are those with the general formula; ; where ;R-^ means a hydroxy-, benzyloxy-, allyloxy-, propargyloxy-, alkylsulfenyl-, alkylsulfinyl-, alkylsulfonyl-, alkylsulfoximino- or aminosulfonyl group, ;R2 means an alkoxy group, and;R4 means a fluorine, chlorine or bromine atom, a cyan, carboxy, aminocarbonyl, alkoxycarbonyl, nitro or amino group, where the alkyl part in each case may contain 1 or 2 carbon atoms, their tautomers and their acid addition salts, in particular their physiologically compatible acid addition salts with inorganic or organic acids. ;According to the invention, the new compounds are produced by the following methods: ;a) Ring closure of any compound produced in the reaction mixture with the general formula; where R 4 is, as stated at the beginning, one of the residues X or Y is a hydrogen atom and the other of the residues X and Y or both residues X and Y is a group with the formula; ; where ;R^ to R^ are as stated at the beginning,;Zlog Z2'SOItl can be the same or different, optionally substituted amino groups or optionally substituted with lower alkyl groups hydroxy or mercapto groups, or Zlog Z2 together means an oxygen or sulfur atom, a ; optionally with an alkyl group with 1 to 3 carbon atoms substituted;imino group, an alkylenedioxy or alkylenedithio group with 2 or 3 carbon atoms each. The ring closure is conveniently carried out in a solvent or a solvent mixture such as ethanol, iso-propanol, glacial acetic acid, benzene, chlorobenzene, toluene, xylene, glycol, glycol monomethyl ether, diethylene glycol dimethyl ether, sulfolane, dimethylformamide, tetralin or in an excess thereof for the preparation of the compound with the general formula II used acylating agent, for example in the appropriate nitrile, anhydride, acid halide, ester, amide or methoiodide, for example at temperatures between 0 and 250°C, 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 ethylate or potassium tert-butylate. However, the cyclization can also be carried out without solvent and/or condensing agent. b) For the preparation of compounds of the general formula I where R 1 denotes an alkylsulfinyl or alkylsulfonyl group: Oxidation of a compound of the general formula ; where ;R2 to R^ are as indicated at the beginning, and;R^<1>means an alkylsulfenyl or alkylsulfinyl group with each 1 to 3 carbon atoms in the alkyl part. The oxidation is preferably carried out in a solvent or a solvent mixture, for example in water, water/pyridine, acetone, glacial acetic acid, dilute sulfuric acid or trifluoroacetic acid, depending on the oxidizing agent used, suitably at temperatures between -80 and 100°C. For the preparation of an alkylsulfinyl compound of the general formula I, the oxidation is suitably carried out with an equivalent of the oxidizing agent used, for example with hydrogen peroxide in glacial acetic acid, trifluoroacetic acid or formic acid at 0 to 20°C or in acetone at 0 to 60°C, with a peracid such as permauric acid in glacial acetic acid or trifluoroacetic acid at 0 to 5 0°C, or with m-chloroperbenzoic acid in methylene chloride or chloroform at -2 0 to 60°C, with sodium metaperiodate in aqueous methanol or ethanol at -15 to 25°C, with bromine in glacial acetic or aqueous acetic acid, with N-bromosuccinimide in ethanol, with tert-butyl hypochlorite in methanol at -80 to -3 0°C, with iodobenzodichloride in aqueous pyridine at 0 to 50°C, with saltpeter -acid in glacial acetic acid at 0 to 20°C, with chromic acid in glacial acetic acid or in acetone at 0 to 20°C and with sulfuryl chloride in methylene chloride at -7 0°C, the thioether-chlorine complex thus obtained being appropriately hydrolyzed with aqueous ethanol. ;For the preparation of an alkylsulfonyl compound with the general formula I, the oxidation is suitably carried out with a resp. with 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°C or in acetone at 0 to 60°C, but a peracid such as performatic acid or m-chloroperbenzoic acid in glacial acetic acid, trifluoroacetic acid , methylene chloride or chloroform at temperatures between 0 and 60°C, with nitric acid in glacial acetic acid at 0 to 2 0°C, with chromic acid or potassium permanganate in glacial acetic acid, water/sulfuric acid or in acetone at 0 to 2 0°C .;c) For the preparation of compounds with the general formula I where means an alkoxy-, phenyl-, cyano-, ;alkylsulfenyl-, alkenyloxy- or alkynyloxy group:; Reaction of a compound with the general formula ; where ;R. is as stated at the beginning, U means a hydroxy or mercapto group, R2 1 means a hydroxy group or has the meanings given for R2 at the beginning, and R3' means a hydroxy group or has the meanings given for R^ at the beginning, with a halide with the general formula; ; where R^means an alkyl, phenylalkyl, cyanoalkyl, alkenyl or alkynyl group, where the alkyl part in each case may contain 1 to 3 carbon atoms and alkenyl or the alkynyl moiety may contain 3 to 5 carbon atoms, and ;W means a nucleophilic leaving group such as a chlorine, bromine or iodine atom. The reaction is conveniently carried out in a solvent such as tetrahydrofuran, dioxane, dimethylformamide, sulfolane, dimethyl sulfoxide 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 100°C, preferably at temperatures between 20 and 50°C.;d) For the preparation of compounds of the general formula I where R^ denotes an alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl or dialkylaminocarbonyl group: Reaction of a benzimidazole with the general formula; where ;R 1til is as indicated at the outset, or its possibly reactive derivative produced in the reaction mixture, with a compound of the general formula ; ; where Rg is an alkoxy, amino, alkylamino or dialkylamino group, where the alkyl part may in each case contain 1 to 3 carbon atoms, or with an optional N-activated amine of the general formula VII formed in the reaction mixture when a carboxylic acid with the general formula VI is used. The method thus concerns the acylation of a compound of the general formula VII with a carboxylic acid of the general formula VI in the presence of an acid-activating or a water-attracting agent, or with functional derivatives thereof, 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 reactive derivatives thereof. As optional functional derivatives of a carboxylic acid with the general formula VI produced in the reaction mixture, for example, its alkyl, aryl or aralkyl esters or thioesters such as the methyl, ethyl, phenyl or benzyl esters, its imidazolide -derivatives, its acid halides such as the acid chloride or bromide, its anhydrides, its mixed anhydrides with aliphatic or aromatic carboxylic, sulfenic, sulfinic or sulfonic acids or carboxylic acid esters, for example with acetic acid, propionic acid, p-toluenesulfonic acid or O-ethylcarbonic acid , its O-triphenylphosphonium complexes, its N-acyl-oxyimides, its azides or nitriles or the corresponding amino-thiocarboxylic acid derivatives, and which optionally in the reaction mixture produced reactive derivatives of an amine with the general formula VI its phosphazo derivatives. As acid-activating and/or water-attracting agents, for example, a chloroformic acid ester such as chloroformic acid ethyl ester, thionyl chloride, phosphorus trichloride, phosphorus pentoxide, N,N'-dicyclohexylcarbodi:ruide, N,N'-carbonyldiimidazole, N,N<*->thionyldiimidazole comes into consideration , boron trifluoride etherate or triphenylphosphine/carbon tetrachloride.

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 at the same time can serve as a solvent, and possibly in the presence of an acid activating agent at temperatures between -25 and 250°C, preferably at temperatures between -10 and the boiling temperature of the solvent used. Herein, any functional derivative of a compound of the general formula VI or VII formed in the reaction mixture does not need to be isolated, and moreover the reaction can also be carried out without a solvent. Furthermore, water formed during the reaction can be separated by azeotropic distillation, for example by heating with toluene in a water separator, or by adding a drying agent such as magnesium sulfate or molecular sieves. e) For the preparation of compounds of the general formula I where an alkylsulfoximino group means: Reaction of a sulfoxide of the general formula

where

R2 to R^ are as indicated at the outset, and

R7 means an alkyl group with 1 to 3 carbon atoms, possibly with hydrogen azide formed in the reaction mixture.

The reaction is suitably carried out in a solvent or a solvent mixture such as methylene chloride, dimethylformamide or tetrahydrofuran, at temperatures between 0 and 40°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 the general formula I where an alkylsulfoximino group means:

Reaction of a sulfoxide with the general formula

where

R 2 to R 1 are as indicated at the outset, and

R₁ means an alkyl group of 1 to 3 carbon atoms, with a compound of the general formula

where

W means a carbonyl or sulfonyl group, and

Rg means an aryl group disubstituted in the o-position such as a 2,4,6-trimethylphenyl or 2,4,6-triisopropylphenyl group.

The reaction is conveniently carried out in a solvent or a solvent mixture such as methylene chloride, chloroform, dimethylformamide, tetrahydrofuran or dioxane, at temperatures between 0 and 50°C, preferably at temperatures between 5 and 40°C, and optionally in the presence of a catalytic amount of an acid such as p-toluenesulfonic acid. The reaction is particularly advantageously carried out by using a compound of the general formula IX without prior isolation or is produced in the reaction mixture.

If, according to the invention, a compound of the general formula I is prepared where R^ means an alkoxycarbonyl, cyano, aminocarbonyl, alkylaminocarbonyl or dialkylaminocarbonyl group, this can be transferred by hydrolysis to a corresponding compound of the general formula I where R^ means a carboxyl group, and/or

if one prepares a compound of the general formula I

where R4 means an aminocarbonyl group, then this can be transferred by dehydration to a corresponding compound with the general formula I where means a cyano group,

and or

if one prepares a compound with the general formula I where R 4 means a nitro group, then this can be transferred by reduction to the corresponding compound with the general formula I where R 4 means an amino group, and/or

if one prepares a compound of the general formula I where R^ denotes an amino group, this can be transferred by carbamoylation to a corresponding compound of the general formula I where R^ denotes an aminocarbonylamino, alkylaminocarbonylamino or dialkylaminocarbonylamino group,

and or

if one prepares a compound of the general formula I where R^ and/or R 2 means a benzyloxy group, then this can be transferred by debenzylation to a corresponding compound of the general formula I where R^ and/or R 2 means 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 12 0°C, for example at temperatures between room temperature and the boiling temperature of the reaction mixture, the partial hydrolysis preferably being carried out with concentrated sulfuric acid.

The subsequent dehydration is carried out with a water-attracting agent such as phosphorus pentoxide, phosphorus oxychloride, sulfuric acid or p-toluenesulphonic acid chloride, optionally in a solvent such as methylene chloride or pyridine, at temperatures between 0 and 100°C, preferably at temperatures between 20 and 80° 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, suitably with hydrogen in the presence of a hydrogenation catalyst such as Raney nickel, platinum or palladium/charcoal, with metals such as iron , tin or zinc, in the presence of an acid, with salts such as ferrous sulphate, stannous chloride, sodium sulphide, sodium hydrogen sulphide or sodium dithionite, or with hydrazine in the presence of Raney nickel at temperatures between 0

and 50°C, preferably at room temperature.

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

The subsequent debenzylation is suitably carried out in

a solvent such as methanol, ethanol, ethyl acetate or glacial acetic acid, using catalytically activated hydrogen, for example with hydrogen in the presence of platinum or palladium/charcoal, at temperatures between 0 and 75°C, preferably at room temperature, and at a hydrogen pressure of 1-5 bars.

Furthermore, the compounds obtained by the general formula I can then optionally be transferred to their physiologically compatible acid addition salts with inorganic or organic acids. As acids, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, fumaric acid, succinic acid, tartaric acid, citric acid, lactic acid, maleic acid or methanesulfonic acid come into consideration.

The compounds with the general formulas II to IX used as starting materials are partly known from the literature or can be prepared by methods known from the literature.

Thus, for example, the compounds of the general formula II used as starting materials are obtained by acylation of a suitable o-diamino compound, and the compounds of the general formulas III, IV, VI and VIII by subsequent condensation with a suitable benzoic acid derivative and possibly subsequent oxidation (see EP-A-0 022 495L.

As mentioned at the outset, the new compounds of the general formula I, their 1H tautomers and their physiologically compatible acid addition salts exhibit superior pharmacological properties with a long duration of action, in particular a blood pressure lowering, positive inotropic and/or antithrombotic effect.

As examples were the compounds

A = 2-(2-methoxy-4-methylsulfonyl-phenyl-1-5-cyano-benzimidazole).

and

B = 2-(2-methoxy-4-propargyloxy-phenyl).-5-cyano-benzimidazole

with regard to its biological properties as follows: Determination of the blood pressure effect and the positive inotropic effect in anesthetized cats

The investigations were carried out on cats that were anesthetized with pentobarbital sodium (40 mg/kg i.p.). The animals breathed spontaneously. The arterial blood pressure was measured in the Aorta abdominalis with a Statham pressure transducer (P 23 Dc). To achieve the positive inotropic effect, the pressure in the left heart chamber was measured with a catheter tip manometer (Millar PC-3 50 A). On this basis, the contractility parameter dp/dt maK,s was determined using an analog differentiator. The test compounds were injected into a femoral vein. Polydiol 200 served as solvent. Each compound was tested in at least 3 cats.

The following table contains the average values found:

The new compounds are well compatible, and thus no cardiotoxic effects or circulatory damage could be observed for compounds A and B during the examination.

Due to their pharmacological properties, the compounds of the general formula I prepared according to the invention and their physiologically compatible acid addition salts are suitable for the treatment of heart insufficiency of various origins, since they increase the contraction force of the heart and facilitate the emptying of the heart when blood pressure is lowered.

For these purposes, the new compounds and their physiologically compatible acid addition salts, possibly in combination with other active substances, can be incorporated into the usual pharmaceutical application forms such as tablets, dragees, powders, suppositories, suspensions, ampoules or drops. The single dose is 1-4 x daily 0.3 - 2.2 mg/kg body weight, preferably 0.7 - 1.5 mg/kg body weight.

The following examples further illustrate the invention: Example 1 2-(2-methoxy-4-methylmercapto-phenyl)-5-methoxycarbonyl-benzimidazole 2 3.9 g of 4-methoxycarbonyl-1,2-phenylenediamine dihydrochloride and 19.8 g of 2-methoxy-4-methylmercapto-benzoic acid is heated with 700 ml of phosphorus oxychloride for 2.5 hours under reflux. The excess phosphorus oxychloride is then distilled off in a vacuum, the crystalline residue is stirred with ice water, concentrated ammonia is added for an alkaline reaction, and the crystals are suctioned off. It is crystallized from 70% ethyl alcohol and dried at 70°C.

Melting point: 206-208°C,

yield: 23.0 g (70% of theoretical).

Analogously, the following compounds are prepared: 2-(2-methoxy-4-ethylImercapto-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-methylImercapto-phenyl)-5-carboxybenzimidazole 10.2 g 2-(2-Methoxy-4-methylmercapto-phenyl)-5-methoxy-

carbonyl-benzimidazole is heated in 3 00 mT.2N caustic soda for 2 hours to boiling under reflux. The mixture is then filtered hot over diatomaceous earth and acidified with 2N hydrochloric acid. Extract with suction, wash with water and dry at 70°C.

Melting point: 308-310°C (decomp.}..,

yield: 8.6 g (88% of the theoretical.

Analogously, the following compounds are prepared: 2-(2-Methoxy-4-e ty Imer capto-phenyl).-5-carboxy-benzimidazole 2-(2-ethoxy-4-n-propyl Imer capto-phenyl). -5-carboxybenzimidazole Example 3

2-(2-Methoxy-4-methylmercapto-phenyl)-5-aminocarbonyl-benzimidazole

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

Melting point: 138-142°C,

yield: 4.5 g (67.4% of theory).

Analogously, the following compounds are prepared: 2-(2-methoxy-4-methylmercapto-phenyl)-5-methylaminocarbonyl-benzimidazole

2-(2-Methoxy-4-methylmercapto-phenyl)-5-ethylaminocarbonyl-benzimidazole

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

2-(2-Methoxy-4-methylmercapto-phenyl)-5-di-n-propylaminocarbonyl-benzimidazole

2-(2-Methoxy-4-ethylmercapto-phenyl)-5-aminocarbonyl-benzimidazole 2-(2-ethoxy-4-methylmercapto-phenyl)-5-methylaminocarbonyl-benzimidazole

2-(2-ethoxy-4-ethylmercapto-phenyl).-5-diethylaminocarbonyl-benzimidazole

2-(2-Methoxy-4-n-propylmercapto-phenyl)-5-aminocarbonyl-benzimidazole

Example 4

2- ( 2- methoxy- 4- methylmer' capto- phenyl)- 5- cyano- benzimidazole

3.5 g of 2-(2-methoxy-4-methylmercapto-phenyl)-5-aminocarbonyl-benzimidazole is heated with 100 ml of phosphorus oxychloride for 2.5 hours under reflux, and then excess phosphorus oxychloride is distilled off in vacuo. The residue is decomposed with ice/water, concentrated ammonia is added for an alkaline reaction and suction is applied. The crystals obtained are dried at 70°C. Melting point: 211-215°C,

yield: 3.05 g (92.4% of theory).

Analogously, the following compounds are prepared: 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

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

Melting point: 115-116°C,

yield: 1.79 g (84.9% of theory).

Analogously, the following compounds are prepared: 2-(2-methoxy-4-ethylsulfinyl-phenyl)-5-cyano-benzimidazole 2-(2-methoxy-4-n-propylsulfinyl^phenyl)-5-cyano-benzimidazole 2-(2- ethoxy-4-methyl sulfinyl-phenyl).-5^-cyano-benzimidazole

Example 6

2-(2-Methoxy-4-methylsulfonyl-phenyl)-5-cyano-benz imidazo 1

0.7 g of 2-(2-methoxy-4-methylmercapto-phenyl)-5-cyano-benzimidazole is dissolved in 10 ml of formic acid, 0.51 ml of hydrogen peroxide (399 mg/ml) is added and allowed to stand for 4 hours. It is then diluted with 40 ml of water, the separated crystals are suctioned off and dried at 60°C.

Melting point: 260-261°C,

yield: 0.71 g (91.5% of theory).

Analogously, the following compounds are prepared: 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

To 0.623 g of 2-(2-methoxy-4-methylsulfinyl-phenyl)-5-cyano-benzimidazole, dissolved in 5 ml of dimethylformamide, 1.43 g of O-mesitylenesulfonyl-acethydroxamic acid ethyl ester and 1.71 g of p-toluenesulfonic acid are added. After 20 hours, 10 ml of water is added and concentrated ammonia is added for an alkaline reaction. The crystallized substance is recrystallized from ethanol. Melting point: 262-263°C (decomp.)>

yield: 0.33 g (50.6% of theory).

Analogously, the following compound is prepared: 2-(2-methoxy-4-ethylsulfoximino-phenyl)-5-cyano-benzimidazole Example 8

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

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

Melting point: 175-178°C,

yield: 53.5% of the theoretical.

Analogously, the following compounds are prepared: 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- behzimidazole

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°C,

yield: 41.6% of the theoretical.

Analogously, the following compounds are prepared: 2-(2-methoxy-4-ethylsulfonyl-phenyl)-5-carbamido-benzimidazole 2-(2-methoxy-4-n-propylsulfonyl-phenyl)-5-carbamido-benzimidazole 2-(2- ethoxy-4-methylsulfonyl-phenyl)-5-carbamido-benzimidazole Example 10

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

Prepared analogously to example 7 from 2-(2-methoxy-4-methylsulfinyl-phenyl)-5-carbamido-benzimidazo and O-mesitylene-acet-hydroxamic acid ethyl ester.

Melting point: 260-262°C,

yield: 41.4% of the theoretical.

Analogously, the following compounds are prepared: 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°C,

yield: 59.2% of the theoretical.

Analogously, the following compounds are prepared: 2-(2-methoxy-4-benzyloxy-phenyl)-5-chloro-benzimidazole 2-(2-methoxy-4-benzyloxy-phenyl)-5-bromo-benzimidazole Example 12

2-( 2- me toxy- 4- hydroxy- phenyl)- 5- fluoro- benzimidaz o1

2.1 g of 2-(2-methoxy-4-benzyloxy-phenyl)-5-fluoro-benzimidazole is catalytically hydrogenated in 100 ml of ethanol with 0.2 g of palladium/charcoal (10%) at 20°C and a hydrogen pressure of 4 bar. The catalyst is then filtered off, the clear solution is evaporated, and the residue is crystallized by trituration with ether. Melting point: 291-293°C,

yield: 87.7% of the theoretical.

Example 13

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

Dissolve 1.22 g of 2-(2-methoxy-4-hydroxy-phenyl)-5-fluoro-benzimidazole in 10 ml of dimethyl sulfoxide, add 0.65 g of anhydrous potassium carbonate, and then add dropwise 0.37 g of chloroacetonitrile, dissolved in 3 ml of dimethylsulfoxide, at 20°C over 35 minutes with stirring. The mixture is stirred for 14 hours, the reaction mixture is introduced into 30 ml of ice water and the pH is adjusted to 5 with 2N acetic acid. The precipitated product becomes crystalline when heated to 70°C. The product is extracted, washed with water and dried at 70°C. For purification, the crude product is chromatographed over a silica gel column with a mixture of methylene chloride/ethyl acetate = 5:1.

Melting point: 18 5-19 0°C,

yield: 0.68 g (48.7% of theory).

Analogously, the following compounds are prepared: 2-(2-methoxy-4-cyanomethylthio-phenyl)-5-fluoro-benzimidazole 2-(2-methoxy-4-allyloxy-phenyl)-5-fluoro-benzimidazole 2-(2-ethoxy- 4-cyano-methoxy-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°C,

yield: 83.1% of the theoretical.

Analogously, the following compounds are prepared: 2-(2-methoxy-4-butyn-2-yloxy-phenyl)-5-nitro-benzimidazole 2-(2-ethoxy-4-propargyloxy-phenyl)-5-nitro-benzimidazole Example 15

2- ( 2- methoxy- 4- propargyloxy- phenyl).- 5- amino- benzimidazole

1.8 g of 2-(2-methoxy-4-propargyloxy-phenyl).-5-nitro-benzimidazole is suspended in 50 ml of glacial acetic acid, heated to 90°C and a solution of 9.4 g of sodium dithionite is added over the course of 15 minutes in 50 ml of water. The light brown solution formed is evaporated in vacuum on a rotary evaporator. The residue is stirred with 50 ml of water, sodium carbonate is added to give an alkaline reaction and extracted three times with a chloroform-methanol mixture = 4:1. The combined extract is dried over magnesium sulfate, evaporated, and the foamy residue is dried in a desiccator. Yield: 0.40 g (4.4% of theoretical),

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

Analogously, the following compounds are prepared: 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-methylaminocarbonylamino-benzimidazole

0.36 g of 2-(2-methoxy-4-propargyloxy-phenyl)-5-amino-benzimidazole is dissolved in 5 ml of tetrahydrofuran, 0.14 g of methyl isocyanate is added and heated for 2 hours at 60°C. Evaporation is then carried out in a vacuum. The residue is purified by column chromatography over silica gel with ethylene chloride/ethanol = 10:1.

Melting point: 2 03-204°C,

yield: 0.34 g (78.9% of the theoretical)..

Analogously, the following compounds are prepared: 2-(2-methoxy-4-butyn-2-yloxy-phenyl)-5-methylaminocarbonyl-amino-benzimidazole

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

2-(2-ethoxy-4-propargyloxy-phenyl 1-5-ethylaminocarbonyl 1-amino-benzimidazole

Example 17

2-(2-Methoxy-4-propargyloxy-phenyl1-5-methoxycarbonyl-benzimidazole

Prepared analogously to example 1 from 3,4-diamino-benzoic acid methyl ester dihydrochloride and 2-methoxy-4-propargyloxy-benzoic acid in boiling phosphorus oxychloride.

Melting point: 116-120°C,

yield: 59.5% of the theoretical.

Analogously, the following compound is prepared: 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 caustic soda.

Melting point: 235-240°C,

yield: 9 2.8% of the theoretical.

Analogously, the following compounds are prepared: 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-phenyl1-5-aminocarbonyl-benzimidazole

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

Melting point: 150-152°C,

yield: 35.0% of the theoretical.

Analogously, the following compounds are prepared: 2-(2-methoxy-4-propargyloxy-phenyl)-5-methylaminocarbonyl-benzimidazole

2-(2-ethoxy-4-propargyloxy-phenyl)-5-aminocarbonyl-benzimidazole 2-(2-methoxy-4-allyloxy-phenyl)-5-aminocarbonyl-benzimidazole 2-(2-methoxy-4-allyloxy-phenyl) )-5-n-propylamino-carbonyl-benzimidazole

Example 2 0

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

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

Melting point: 243-245°C,

yield: 85.0% of the theoretical.

Analogously, the following compound is prepared: 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 heated in 50 ml of dry chlorobenzene

for 5 hours until boiling under reflux. During this time crystals of (2-methoxy-4-aminosulfonyl)-benz-(2-nitro-4-cyano)-anilide are separated from the initially clear solution. They are sucked off while hot, washed with cold chlorobenzene and then with ethyl acetate and dried at 60°C.

Melting point: 270-274°C,

yield: 2.47 g (72.9% of theory).

b) 2.40 g of the substance obtained according to example a) is slurried in 2 50 ml of glacial acetic acid, 20 g of iron powder is added and heated for 1.5 hours to boiling under reflux cooling. The iron residue is filtered off, ethyl acetate is distilled off in a vacuum and the residue is stirred with water. The separated crystals are filtered off and chromatographed on a silica gel column with methylene chloride/ethyl acetate = 1:1. White crystals of 2-(2-methoxy-4-aminosulfonyl-phenyl)-5-cyano-benzimidazole are obtained.

Melting point: 284-286°C,

yield: 0.455 g (21.7% of theory).

Analogously, the following compounds are prepared: 2-(2-methoxy-4-methylaminosulfonyl-phenyl). -5-cyano-benzimidazole 2-(2-methoxy-4-dimethylaminosulfonyl-phenyl5-cyano-benzimidazole 2-(2-ethoxy-4-aminosulfonyl-phenyl)-5-cyano-benzimidazole 2-(2-ethoxy -4-methylaminosulfonyl-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-methoxy-4-di-n-propylaminosulfonyl-phenyl)-5-cyano-benzimidazole

Example 2 2

2-(2-Methoxy-4-aminosulfonyl-phenyl)-5-methoxycarbonyl-benzimidazole

Prepared analogously to example 1 from 2-methoxy-4-aminosulfonyl-benzoic acid and 3,4-diamino-benzoic acid methyl ester in boiling phosphorus oxychloride.

Melting point: 284-28 6°C,

yield: 48.4% of the theoretical.

Analogously, the following compounds are prepared: 2-(2-methoxy-4-methylaminosulfonyl-phenyl)-5-methoxycarbonyl-benzimidazole

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

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

Example 2 3

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 caustic soda.

Melting point: 321-323°C,

yield: 61.5% of the theoretical.

Analogously, the following compounds are prepared: 2-(2-methoxy-4-methylaminosulfonyl-phenyl)-5-carboxy-benzimidazole

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

Example 2 4

2-(2-Methoxy-4-aminosulfonyl-phenyl)-5-aminocarbonyl-benzimidazole

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: 7 6.0% of the theoretical.

Analogously, the following compounds are prepared: 2-(2-methoxy-4-aminosulfonyl-phenyl)-5-methylaminocarbonyl-benzimidazole

2-(2-Methoxy-4-methylaminosulfonyl-phenyl)-5-amino-carbonyl-benzimidazole

2-(2-Methoxy-4-dimethylaminosulfonyl-phenyl)-5-aminocarbonyl-benzimidazole

2-(2-Methoxy-4-di-n-propylaminosulfonyl-phenyl)-5-aminocarbonyl-benzimidazole

2-(2-Methoxy-4-aminosulfonyl-phenyl)-5-di-n-propylaminocarbonyl-benzimidazole

Example 2 5

2- ( 2- methoxy- 4- aminosulfonyl- phenyl),- 5- aminocarbonyl- benzimidazole

0.657 g of 2-(2-methoxy-4-aminosulfonyl-phenyl).-5-cyano-benzimidazole is introduced portionwise into 2 ml of concentrated sulfuric acid

and allowed to stand at 30°C for 24 hours. Then decompose with ice, suck off the separated crystals and wash them acid-free. Melting point: 311.5-313.5°C,

yield: 6 0.0% of the theoretical.

Claims (3)

1. Analogous method for the preparation of therapeutically active benzimidazole derivatives of the general formula where R-^ means a hydroxy-, alkoxy-, phenylalkoxy-, cyanoalkoxy-, alkylsulfenyl-, alkylsulfinyl-, alkylsulfonyl-, aminosulfonyl-, alkylaminosulfonyl, dialkylaminosulfonyl, alkylsulfoximino, alkenyloxy or alkynyloxy group, R2 means a hydrogen atom, a hydroxy, alkyloxy, phenylalkyloxy, amino, alkylamino or dialkylamino group, R-, means a hydrogen atom or an alkoxy group, and R^ means a hydrogen or halogen atom, a cyano-, nitro-, amino-, carboxy-, alkoxycarbonyl-, aminocarbonyl-, alkylaminocarbonyl-, dialkylaminocarbonyl-, aminocarbonylamino-, alkylaminocarbonylamino- or dialkylaminocarbonylamino group, where the alkyl part in each case may contain 1 to 3 carbon atoms and the alkenyl or alkynyl part in each case 3 to 5 carbon atoms, their tautomers and their acid addition salts, characterized by ata) an optionally produced compound in the reaction mixture with the general formula where R^ is, as stated above, one of the residues X or Y means a hydrogen atom and the other of the two residues X and Y or both residues X and Y means a group with the formula where R-^ to R^ are as indicated above, Z 1 and Z 2 , which may be the same or different, mean optionally substituted amino groups or optionally substituted with lower alkyl groups hydroxy or mercapto groups, or Z^ and Z2 together mean an oxygen or sulfur atom, an optionally substituted imino group with an alkyl group with 1 to 3 carbon atoms, an alkylenedioxy or alkylenedithio group with 2 or 3 carbon atoms each, are closed, or b) for the preparation of compounds of the general formula I where R 1 means an alkylsulfinyl or alkylsulfonyl group, a compound with the general formula is oxidized where R2 to R4 are as indicated above, and R^' means an alkylsulfenyl or alkylsulfinyl group each having 1 to 3 carbon atoms in the alkyl part, or c) for the preparation of compounds of the general formula I where R 1 denotes an alkoxy, phenyl alkoxy, cyano alkoxy, alkylsulfenyl, alkenyloxy or alkynyloxy group, a compound of the general formula is reacted where R. is, as stated above, U means a hydroxy or mercapto group, R2<1> means a hydroxy group or has the meanings given for R2 above, and R-,' means a hydroxy group or has the meanings given for R^ above, with a halide of the general formula where R- means an alkyl, phenylalkyl, cyanoalkyl, alkenyl or alkynyl group, the alkyl part in each case may contain 1 to 3 carbon atoms and alkenyl or the alkynyl moiety every 3 to 5 carbon atoms, and W means a nucleophilic leaving group such as a chlorine, bromine or iodine atom, or d) for the preparation of compounds of the general formula I where R 1 means an alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl or dialkylaminocarbonyl group, react a benzimidazole of the general formula where <R> ;L to R^ is as indicated above, or its possibly reactive derivative produced in the reaction mixture, with a compound of the general formula where Rg means an alkoxy, amino, alkylamino or dialkylamino group, where the alkyl part can in each case contain 1 to 3 carbon atoms, or with an N-activated amine of the general formula VII formed in the reaction mixture, if any, when a carboxylic acid of the general formula VI is used, or e) for the preparation of compounds of the general formula I where R 1 denotes an alkylsulfoximino group, a sulfoxide of the general formula is reacted where R 2 to R 1 are as indicated above, and R- means an alkyl group with 1 to 3 carbon atoms, with optionally hydrogen azide formed in the reaction mixture, or f) for the preparation of compounds of the general formula I where R-^ means an alkylsulfoximino group, a sulf- oxide with the general formula where R 2 to R 3 are as indicated above, and R- means an alkyl group of 1 to 3 carbon atoms, with a compound of the general formula where W means a carbonyl or sulfonyl group, and Rg means an aryl group disubstituted in the o-position such as a 2,4,6-trimethylphenyl or 2,4,6-triisopropylphenyl group, and optionally then a thus prepared compound of the general formula I where R 4 means an alkoxycarbonyl, cyano, aminocarbonyl, alkylaminocarbonyl or dialkylaminocarbonyl group is transferred by hydrolysis to a corresponding compound of the general formula I where R 4 means a carboxyl group, and/ or a prepared compound of the general formula I where R 4 means an aminocarbonyl group is transferred by dehydration to a corresponding compound of the general formula I where R 4 means a cyano group, and/or a prepared compound of the general formula I where R 4 means a nitro group is transferred by reduction to a corresponding compound of the general formula I where R 4 means an amino group, and/or a prepared compound of the general formula I where R 4 means an amino group is transferred by carbamoylation to a corresponding compound of the general formula I where R 4 means an aminocarbonylamino, alkylaminocarbonylamino or dialkylaminocarbonylamino group, and/or a prepared compound of the general formula I where R1 and/or R2 means a benzyloxy group is transferred by debenzylation to a corresponding compound of the general formula I where R-^ and/or R2 means a hydroxy group, and/or a prepared compound with the general formula I is transferred to its acid addition salt, in particular to its physiologically compatible acid addition salt with an inorganic or organic acid. 2. Process according to claim 1, characterized in that 2-(2-methoxy-4-methylsulfonyl-phenyl)-5-cyano-benzimidazole is produced. 3. Process according to claim 1, characterized in that 2-(2-methoxy-4-propargyloxy-phenyl)-5-cyano-benzimidazole is produced.