DE2837161A1 - 5-Alkyl:pyridazinyl substd. benzimidazole derivs. - useful as cardiovascular agents, antivirals, interferon inducers and ulcer inhibitors - Google Patents

Abstract

Benzimidazole derivs. of formula (I) and their optical antipodes when A = B = H, and their physiologically acceptable salts with organic or inorganic acids are new: (A and B are each H, or together make a double bond; R1 = H, CF3, 1-11C alkyl, 3-7C cycloalkyl, OH or SH (both opt. etherified with 1-6C alkyl), phenyl (1-3C) alkyl, or phenyl (opt. substd. by 1-3 same or different halo, 1-4C alkyl, 1-6C alkylsulphinyl, OH or SH, both the latter opt. etherified with 1-6C alkyl); R2 = H, 1-5C alkyl, 3-6C cycloalkyl or phenyl (1-3C) alkyl; R3 = 1-6C alkyl). (I) have antiviral, interferon-inducing, ulcer-inhibiting and esp. cardiovascular (cardiotonic, hypotensive and/or antithrombotic) activities.

Description

Description:

The present application relates to new benzimidazoles of the general formula their physiologically acceptable acid addition salts with inorganic or organic acids, processes for their preparation and medicaments containing these compounds.

The compounds of the above general formula I and their physiological Compatible acid addition salts have valuable pharmacological properties on, in particular cardiovascular effects, namely cardiotonic, antihypertensive and / or antithrombotic.

In the above general formula I, A and B each represent a hydrogen atom or together another bond, R1 a hydrogen atom, the trifluoromethyl group, an alkyl group having 1 to 6 carbon atoms, a cycloalkyl group having 3 to 7 carbon atoms, one optionally through an alkyl group having 1 to 6 carbon atoms substituted Hydroxyl or mercapto group or a phenyl group, by a halogen atom, an alkyl group having 1 to 4 carbon atoms and / or one optionally substituted by an alkyl group having 1 to 3 carbon atoms Hydroxy or mercapto group can be mono-, di- or trisubstituted, the Substituents of the phenyl nucleus can be identical or different, R2 is a hydrogen atom, an alkyl group with 1 to 3 carbon atoms or a cycloalkyl group with 3 - 6 carbon atoms and R3 is an alkyl group with 1 to 6 carbon atoms.

Preferred compounds of the general formula I here are those in which A and B each have a hydrogen atom or together a further bond, R1 Hydrogen atom, the trifluoromethyl group, an alkyl group with 1 to 6 carbon atoms like the methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec. butyl, tert-butyl, n-pentyl, tert-pentyl, isopentyl or n-hexyl group, a cycloalkyl group with 3 to 7 carbon atoms such as the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl group, optionally substituted by an alkyl group having 1 to 6 carbon atoms substituted hydroxyl or mercapto group such as the hydroxyl, methoxy, ethoxy, Propoxy, isopropoxy, mercapto, methyl mercapto, ethyl mercapto, propyl mercapto, Hexyl mercapto or isopropyl mercapto group, a phenyl group that is replaced by a halogen atom, an alkyl group with 1 to 4 carbon atoms, a hydroxy, methoxy, mercapto and / or methyl mercapto group can be mono- or disubstituted, such as the fluorophenyl, Difluorophenyl, chlorophenyl, dichlorophenyl -, bromophenyl, dibromophenyl, Methylphenyl, dimethylphenyl, hydroxyphenyl, dihydroxyphenyl, methoxyphenyl, Dimethoxyphenyl, t-5ercaptophenyl, dimercaptophenyl, methyl mercaptophenyl, dimethyl mercaptophenyl, Fluoro-hydroxyphenyl-, fluoro-methoxyphenyl-, fluoro-mercaptophenyl-, fluoro-methylmercaptophenyl-, Chloro-hydroxyphenyl-, chloromethoxyphenyl-, chloro-mercaptophenyl-, chloro-methylmercaptophenyl-, Bromohydroxyphenyl, bromomethoxyphenyl, bromomercaptophenyl, bromomethulmercaptophenyl, Hydroxy-methoxyphenyl-, hydroxy-mercaptophenyl-, hydroxy-methylmercaptophenyl-, Methoxy-mercaptophenyl or methoxy-methylmercaptophenyl group, R2 is a hydrogen atom, the methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl group and R3 is an alkyl group having 1 to 4 carbon atoms such as the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or Mean tert-butyl group, as well as their physiologically acceptable acid addition salts with inorganic or organic acids.

However, particularly preferred compounds of the general formula I are those in which A and B each have a hydrogen atom or together another bond, R1 is a hydrogen atom, the methyl, n-hexyl, isopropyl, 1-pentyl, 2-pentyl, Cyclopropyl, cyclohexyl, hydroxy, methyl mercapto, hexyl mercapto, trifluoromethyl, 2-fluorophenyl, 2,4-difluorophenyl, 2-methoxyphenyl, 4-methoxyphenyl, 2,4-dimethoxyphenyl, 3,4-dimethoxyphenyl-, 4- Methyl mercaptophenyl, 2-methyl mercaptophenyl, 2,4-dimethylmercaptophenyl-, 2-methoxy-4-methylmercaptophenyl-, 2-methoxy-5-mercaptophenyl-, 4-tert-butylphenyl or 2-methylmercapto-4-methoxyphenyl group, R2 is a hydrogen atom, the methyl, cyclopropyl or cyclohexyl group and R3 the methyl group, and their physiologically compatible acid addition salts with inorganic or organic acids.

Furthermore, the new benzimidazoles of the present application in their 1 H or 3 H tautomers and due to their optically active carbon atom in the 5-position of the pyridazine ring, if A and B each represent a hydrogen atom, occur in the form of their racemate or their optically active antipodes.

According to the invention, the new benzimidazoles, their racemates and optically active antipodes, if A and B each represent a hydrogen atom, can be prepared by the following processes: a) Cyclization of a compound of the general formula which may be prepared in the reaction mixture in which A, B, R2 and R3 are as defined at the outset, one of the radicals X or Y is a hydrogen atom and the other of the radicals X or Y is a group of the formula represents, in which Z1 and Z2, which can be the same or different, optionally substituted by lower alkyl groups, hydroxy or mercapto groups or Z1 and Z2 together an oxygen or sulfur atom, an imino group optionally substituted by an alkyl group with 1 to 3 carbon atoms, an alkylenedioxy or alkylenedithio group each having 2 or 3 carbon atoms and R4 has the meanings mentioned for R1 at the beginning or represents an amino group optionally substituted by an alkyl group having 1 to 3 carbon atoms, or their alkali metal salts if R4 represents the mercapto group.

The cyclization is conveniently carried out in a solvent such as Ethanol, isopropanol, glacial acetic acid, chlorobenzene, glycol, dimethylformamide, tetralin or in an excess of that for the preparation of the compound of the general formula II used acylating agent, e.g. in R1CN, (R1CO) 20, R1COOH, R1CSOH or R1CSSH and their esters, amides or halides, at elevated temperatures, e.g. between 0 and 2500C, optionally in the presence of a condensing agent such as Phosphorus oxychloride, thionyl chloride, Sulfuryl chloride, sulfuric acid, Hydrochloric acid, phosphoric acid, polyphosphoric acid, glacial acetic acid, acetic anhydride or optionally also carried out in the presence of a base such as potassium ethylate or potassium tert-butoxide. However, the cyclization can also be carried out without a solvent and / or without a condensing agent be performed.

However, the implementation is particularly advantageously carried out in such a way that a corresponding 6- (acylamino-nitro-phenyl) -pyridazin-3-one by reduction, for example by reduction with hydrogen in the presence of a hydrogenation catalyst like Raney nickel, platinum or palladium / carbon, by reduction with metals like Iron, tin or zinc or by reduction with metal salts such as iron (II) sulfate, Tin (II) chloride or chromium (II) chloride, in a corresponding compound of the general Formula II is converted, which optionally in the same reaction mixture if necessary in the presence of an acid such as hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid or a carboxylic acid of the formula R1COOH, or in the presence of a condensing agent such as phosphorus oxychloride or optionally in the presence of a base such as potassium ethylate in a solvent such as ethanol, isopropanol, glycol, dimethylformamide, dimethyl sulfoxide or chlorobenzene is cyclized at temperatures between 0 and 2500C.

For the preparation of a compound of the general formula I in which R1 represents the mercapto group, the reaction is expediently in the manner carried out that a compound of general formula II in situ by reaction a corresponding 7,8-diamino compound with carbon disulfide in the presence an alkali alcoholate, e.g. in the presence of potassium ethylate, in an alcoholic Solvent such as ethanol is made. The subsequent cyclization takes place by simply heating the reaction mixture, preferably by heating the boiling point of the reaction mixture.

b) Implementation of a carboxylic acid of the general formula in which A, B, R1, R2 and R3 are as defined at the outset, or their esters, amides or halides with hydrazine.

The reaction is expediently carried out in a solvent such as ethanol, Isopropanol, glacial acetic acid, propionic acid and / or in an excess of hydrazine or Hydrazine hydrate at elevated temperatures, e.g. at temperatures between 0 and 1500C, and optionally in the presence of an acid as a condensing agent such as sulfuric acid or p-toluenesulfonic acid. However, the reaction can also be carried out without a solvent be performed.

A compound obtained according to process a) or b) of the general Formula I, in which A and B each represent a hydrogen atom, can then, if desired by dehydration into a compound of the general formula I, in which A and B together represent another bond, be converted and / or a compound obtained of the general formula I, in which R1 is the hydroxyl or mercapto group or a phenyl group, those mono-, di- or trisubstituted by a hydroxy and / or mercapto group is, and / or R2 is a Represents hydrogen atom by means of alkylation into a corresponding alkoxy, alkyl mercapto and / or alkyl compound of the general Formula I are converted, and / or a compound obtained from the general Formula I, in which R1 represents an alkyl mercapto group, by means of oxidation and then hydrolytic cleavage of the alkylsulfinyl or alkylsulfonyl group formed be converted into a corresponding hydroxy compound of the general formula I.

Post dehydration is done with a dehydrating agent such as bromine, phosphorus pentachloride, sodium 3-nitrobenzenesulfonic acid, chromium trioxide, N-bromosuccinimide, hydrogen peroxide or sodium nitrite in a solvent such as Glacial acetic acid, propionic acid, water / glacial acetic acid or nitrobenzene at temperatures between 0 and 1000C, but preferably at temperatures between 50 and 80C.

Post-alkylation is carried out with an alkylating agent such as an alkyl halide, dialkyl sulfate, trialkyloxonium tetrafluoroborate or diazoalkane, e.g. with methyl iodide, dimethyl sulfate, diethyl sulfate, ethyl bromide or diazomethane, expediently in a solvent such as methanol, ethanol, methanol / water, Diethyl ether or dioxane, if appropriate in the presence of a base such as sodium bicarbonate, Sodium carbonate, sodium hydroxide or potassium carbonate at temperatures up to the boiling point of the solvent used.

Furthermore, the compounds of general formula I obtained, in which A and B each represent a hydrogen atom, in their optically active antipodes be separated by means of racemate resolution. The resolution is expedient by fractional crystallization of the corresponding salts with optically active ones Acids such as tartaric acid, dibenzoyltartaric acid, malic acid, camphoric acid or camphorsulphonic acid carried out.

Furthermore, the compounds of the general formula obtained can I if desired into their physiologically acceptable salts with inorganic or organic acids are converted. The acids come for this, for example Hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, fumaric acid, succinic acid, Lactic acid, citric acid, tartaric acid or maleic acid can be considered.

The compounds of the general formulas II and III used as starting materials are obtained by processes known from the literature (see BE-PS 830 030). For example, a compound of the general formula III is obtained by reacting a compound of the general formula with malonic ester. The compound obtained in this way is then saponified, decarboxylated, nitrated, the chlorine atom replaced by a corresponding amino group, acylated, the nitro group reduced and cyclized to give the desired benzimidazole.

The compounds of the present application differ from those of Belgian patent 830 030 by the alkyl substituent R3 in the 5-position of the pyridazine ring, and surprisingly, the new benzimidazoles also have greater potency and / or better oral absorption.

The new compounds of the present application thus have how already mentioned at the outset, superior pharmacological properties with good oral absorption Properties, in particular cardiovascular effects, namely cardiotonic, antihypertensive and / or antithrombotic.

For example, the compounds A = 2-methyl-5 (6) - (5-methyl-3-oxo-4,5-dihydro-2H-6-pyridazinyl) benzimidazole, B = 2-methyl-5 (6) - (5-methyl-3-oxo-2H-6-pyridazinyl) -benzimidazole, C = 2-trifluoromethyl-5 (6) - (5-methyl-3-oxo-4 , 5-dihydro-2H-6-pyridazinyl) benzimidazole, D = 5 (6) - (5-methyl-3-oxo-4,5-dihydro-2H-6-pyridazinyl) -benzimidazole, E = 2- (2-fluorophenyl) -5 (6) - (5-methyl -3-oxo-4,5-dihydro-2H-6-pyridazinyl) benzimidazole, F = 2-t2,4-dimethoxyphenyl) -5 (6) - (5-methyl-3-oxo-4,5-dihydro-2H-6-pyridazinyl) -benzimidazole, G = 2-methylmercapto-5 (6) - (5-methyl-3-oxo-4,5-dihydro-2H-6-pyridazinyl) benzimidazole, H = 2- (4-methoxy-phenyl) -5 (6) - (5-methyl-3-oxo-4,5-dihydro-2H-6-pyridazinyl) -benzimidazole and I = 2- (4-methyl-phenyl) -5 (6) - (5-methyl-3-oxo-4,5-dihydro-2H-6-pyridazinyl) -benzimidazole examined for their biological properties as follows: 1. Determination platelet aggregation according to Born and Cross (J. Physiol. 170, 397, (1964)): Platelet aggregation was observed in platelet-rich plasma from healthy test subjects measured. Here, the course of the decrease in optical density after addition of commercially available collagen from Sigma, St. Louis / USA, which contains 1 mg of collagen fibrils per ml, measured photometrically and registered. From the angle of inclination of the The density curve was inferred from the aggregation rate (Vmax). The point the curve with the greatest light transmission was used for the calculation the optimal density "(O.D.). Approx. 0.01 ml of the collagen solution added to 1 ml of platelet rich plasma.

The following table contains the values found: Table 1 Compound EC50 in pmoles / l A 0.01 B 34 C 0.1 D 0.12 2. Determination of the antihypertensive and positive inotropic effect on the anesthetized cat: The studies were carried out on cats that were anesthetized with pentobarbital Na (40 mg / kg ip). The animals breathed spontaneously. The arterial blood pressure was measured in the abdominal aorta with a Statham pressure transducer (P 23 Dc). To determine the positive inotropic effect, the pressure in the left ventricle of the heart was measured with a catheter tip manometer (Millar PC-350 A). The contractility parameter dp / dtmaX was obtained from this by means of an analog differentiator.

The substances to be examined were injected into a femoral vein. Physiological saline solution or polydiol 200 served as solvent. Each Substance was tested on 3 cats, dose 2 mg / kg i.v.

The following table contains the mean values from 3 tests each: Substance decrease in blood pressure increase of in mm Hg dp / dt in% Max A - 61/53 + 67 BO + 31 C - 36/35 + 49 D - 57/71 + 97 E - 60/53 + 132 F - 66/65 + 66 G - 35/40 + 7 H - 22/22 + 133 - - 10/20 + 134 3. Acute toxicity The acute toxicity of the substances to be investigated was determined as an orientation in white mice after oral administration of a single dose (observation time: 14 days): Table III Substance acute toxicity mg / kg po A> 600 (1 of 3 animals died) C> 450 (0 of 6 animals died) E> 600 (0 of 6 animals died) HN 600 (3 of 6 animals died) I> 600 (0 of 6 animals died) Due to their pharmacological properties, the compounds of general formula I prepared according to the invention and their optically active antipodes and their physiologically acceptable acid addition salts with inorganic or organic acids are suitable for the treatment of chronic heart failure or angina pectoris and / or for the prophylaxis of arterial thromboembolism and arterial occlusive diseases .

For this purpose, the new benzimidazoles can optionally be combined with other active substances in the usual pharmaceutical application forms such as Incorporate tablets, coated tablets, powders, suppositories, suspensions, ampoules or drops.

The single dose is 25-200 mg 1-4 times a day, preferably but 50-150 mg.

Since the compounds of general formula I in their tautomeric forms 1 H or 3 H can be present, the substitution site on the benzimidazole nucleus was with 5 (6).

The following examples are intended to explain the invention in more detail: example 1 2- (4-methoxyphenyl) -5 (6) - (5-methyl-3-oxo-4,5-dihydro-2H-6-pyridazinyl) benzimidazole hydrochloride a) 3- / 3-Nitro-4- (4-methoxy-benzoylamino) -benzoyl / -butyric acid methyl ester 10 g 3- (3-nitro-4-aminobenzoyl) -butyric acid methyl ester are with 10.2 g of 4-anisyl chloride in 100 ml of chlorobenzene until complete Reaction of the 3- (3-nitro-4-aminobenzoyl) butyric acid methyl ester heated to reflux. The reaction mixture is stirred with activated charcoal, filtered and the filtrate with Cyclohexane is added, the product crystallizing out. It is sucked off and washed with cyclohexane and petroleum ether.

Yield: 10.7 g (73% of theory), melting point: 107-117 ° C.

b) 5-methyl-6- / 3-nitro-4- (4-methoxy-benzoylamino) -phenyl7-3-oxo-4 , 5-dihydro-2H-pyridazine 20 ml of 80% hydrazine hydrate are stirred and cooled with ice added dropwise to 150 ml of glacial acetic acid. After cooling, 10.7 g of 3- / 3-nitro-4- (4-methoxy-benzoylamino) -benzoyl / -butyric acid methyl ester added and the mixture heated to reflux for 40 minutes. After cooling it will 250 ml of ice water are added, the precipitate is filtered off with suction and washed with ice water.

Yield: 9.8 g (96% of theory), melting point: 2190C c) 5-methyl-6-L3-amino-4- (4-methoxy-benzoylamino) -phenyly-3-oxo-4,5-dihydro-2H-pyridazine 9.8 g of 5-methyl-6- [3-nitro-4- (4-methoxy-benzoylamino) -phenyl-3-oxo-4,5-dihydro-2H-pyridazine are dissolved in 1000 ml of ethanol and 23 hours at room temperature with hydrogen hydrogenated by 5 at pressure in the presence of 1 g of 10% palladium-carbon. The resulting Precipitate is filtered off with suction and without separation from the catalyst in the next stage used. Another fraction of the product can be obtained from the mother liquors will.

Yield: 8.5 g (94.4% of theory).

d) 2- (4-Methoxy-phenyl) -5 (6) - (5-methyl-3-oxo-4,5-dihydro-2H-6-pyridazinyl) benzimidazole hydrochloride The product obtained under c) is dissolved in 100 ml of glacial acetic acid Heated to reflux for 1.5 hours and filtered through a glass frit while still hot. 100 g of ice are added to the filtrate and the orange-yellow precipitate that forms is filtered off and washed with dilute acetic acid. The combined filtrates are made alkaline with ammonia. The failed product is after it is crystallized, filtered off with suction and passed through a silica gel column (eluent: methylene chloride / ethanol = 50: 1 and 25: 1) cleaned. The hydrochloride is made from methanol with ethereal hydrochloric acid pleases.

Yield: 4.45 g (49.8% of theory), melting point: 311 ° C. (decomposition).

Example 2 2- (4-Methoxy-phenyl) -5 (6) - (5-methyl-3-oxo-4,5-dihydro-2H-6-pyridazinyl) -benzimidazole hydrochloride a) 2- (4-Methoxy-phenyl) -5 (6) - (1-oxo-2-methyl-3-methoxy-carbonyl-1-propyl) -benzimidazole hydrochloride 9.2 g of 5-methyl-6- / 3-nitro-4- (4-methoxy-benzoylamino) -phenyl5-3-oxo-4,5-dihydro-2H-pyridazine are in a mixture of 300 ml of methanol and 3 ml of glacial acetic acid for 2.5 hours at room temperature hydrogenated with hydrogen at 5 atm. pressure in the presence of 2 g of 10% strength palladium-carbon. Hydrochloric acid gas is passed into the reaction mixture under reflux for 2.5 hours. Thereafter, ether is added, suction filtered and washed with ether.

Yield: 4.5 g (50.5% of theory), melting point: over 3000C.

b) 2- (4-Methoxy-phenyl) -5 (6) - (5-methyl-3-oxo-4,5-dihydro-2H-6-pyridazinyl) -benzimidazole hydrochloride 1 ml of 80% hydrazine hydrate is dissolved in 1C ml of glacial acetic acid and, after cooling, 0.43 g 2- (4-methoxyphenyl) -5 (6) - (1-oXo-2-methyl-3-methoxycarbonyl-1-propyl) benzimidazole hydrochloride added, the precipitated product filtered off with suction, washed with water and over a Purified silica gel column (eluent: chloroform / methanol = 50: 1). The hydrochloride is precipitated from ethanol with essential hydrochloric acid.

Yield: 0.3 g (70.3% of theory), melting point: 314 ° C. (decomposition).

Example 3 2-Methyl-5 (6) - (5-methyl-3-oxo-4,5-dihydro-2E1-6-pyridazinyl) benzimidazole hydrochloride 29 g of 5-methyl-6- (3-nitro-4-acetaminophenyl) -3-oxo-4,5-dihydro-2H-pyridazine become in a mixture of 1200 ml of methanol and 100 ml of glacial acetic acid at room temperature 2.5 Hours with hydrogen at 5 atm pressure in the presence of 5 g of 10% of the palladium-carbon hydrogenated. The catalyst is filtered off and the filtrate is evaporated. The residue is dissolved in 400 ml of glacial acetic acid and heated to 1000C for 40 minutes. The reaction mixture is poured onto 1 l of ice and cooled by adding concentrated ammonia brought to pH 8. The precipitated free base is finally transferred by dissolving in methanol and adding essential hydrochloric acid to the hydrochloride.

Yield: 19.7 g (70.7% of theory), melting point: 3080C.

Example 4 2-Methyl-5 (6) - (5-methyl-3-oxo-2H-6-pyridazinyl) -benzimidazole 8 g of 2-methyl-5 (6) - (5-methyl-3-oxo-4,5-dihydro-2H-6-pyridazinyl) -benzimidazole hydrochloride are suspended in 250 ml of glacial acetic acid and added dropwise with stirring at 700C a solution of 3 ml of bromine in 30 ml of glacial acetic acid was added. After the addition is complete is held at 700C for a further 1 hour, cooled and the oily product which has precipitated out crystallized by adding 20 ml of water and brief heating. The crystallizate is suctioned off, triturated with concentrated ammonia, washed with water and recrystallized from methanol / water.

Yield: 5.6 g (89% of theory), melting point: over 3000C.

Example 5 2- (4-Methoxyphenyl) -5 (6) - (5-methyl-3-oxo-2H-6-pyridazinyl) -benzimidazole Prepared analogously to Example 4 from 0.74 g of 2- (4-methoxyphenyl) -5 (6) - (5-methyl-3-oxo-4,5-dihydro-2H-6-pyridazinyl) benzimidazole hydrochloride and 0.33 ml of bromine. The product is passed through a silica gel column (eluent: chloroform / methanol = 50: 1) cleaned.

Yield: 0.35 g (52.6% of theory), melting point: over 3000C.

Example 6 2- (2,4-Dimethoxyphenyl) -5 (6) - (5-methyl-3-oxo-4,5-dihydro-2H-6-pyridazinyl) Benzimidazole hydrochloride a) 2- (2,4-Dimethoxyphenyl) -5 (6) - (1-oxo-2-methyl-3-ethoxy carbonyl-1-propyl) -benzimidazole hydrochloride Prepared analogously to Example 2a) from 12.2 g of 5-methyl-6-t3-nitro-4- (2,4-dimethoxy-benzoylamino) -pheny-3-oxo-4,5-dihydro-2H-pyridazine. The imidazole ring is made with ethanolic hydrochloric acid closed. The product is only roughly cleaned and further processed in this form.

Yield: 4 g (31.2% of theory).

b) 2- (2,4-Dimethoxyphenyl) -5 (6) - (5-methyl-3-oxo-4,5-dihydro-2H-6-pyridazinyl) -benzimidazole hydrochloride Manufactured analogously to Example 2b from the product obtained under 6a.

Yield: 0.78 g (21.1% of theory), melting point: 266 ° C.

Example 7 2- (4-Methyl-phenyl) -5 (6) - (5-methyl-3-oxo-4,5-dihydro-2H-6-pyridazinyl) -benzimidazole hydrochloride Prepared analogously to Example 2b from 1.5 g of 2- (4-methylphenyl) -5 (6) - (1-oXo-2-methyl-3-methoxycarbonyl-1-propyl) -benzimidazole hydrochloride.

Yield: 0.24 g (16.5% of theory), melting point: 340 ° C. (decomposition).

Example 8 2- (4-methyl-phenyl) -5 (6) - (5-methyl-3-oxo-4,5-dihyaro-2H-6-pyridaz ynyl) benzimidazole hydrochloride Prepared analogously to Example 1d from 21.5 g of 5-methyl-6-fl2-amino-4- (4-methyl-benzoylamino) -phenyl2-3-oxo-4,5-dihydro-2H-pyridazine (Chromatographic purification is not required).

Yield: 18.8 g (82.7% of theory), melting point: 3400C (decomposition) Example 9 2-Cyclopropyl-5 (6) - (5-methyl-3-oxo-4,5-dihydro-2H-6-pyridazinyl) -benzimidazole hydrochloride Prepared analogously to Example 6 from 2.3 g of 5-methyl-6- (3-nitro-4-cyclopropylcarbonylamino-phenyl) -3-oxo-4,5dihydro-2H-pyridazine.

Yield: 1.35 g (61.2% of theory), melting point: 235-237 ° C. (decomposition).

Example 10 1,2-Dimethyl-5 (6) - (5-methyl-3-oxo-4,5-dihydro-2H-6-pyridazinyl) -benzimidazole a) 5-Methyl-6- (3-amino-4-acetyl-methylamino-phenyl) -3-oxo-4,5-dihydro-2H-pyridazine 0.65 g of 5-part ethyl 6- (3-nitro-4-acetyl-methylamino-phenyl) -3-oxo-4,5-dihydro-2H-pyridazine are dissolved in 30 ml of ethanol and treated with 0.5 ml of 80% hydrazine hydrate and 0.5 g of Raney nickel added and heated to 30 ° C for 10 minutes. The catalyst is filtered off, the Glacial acetic acid was added to the filtrate and the mixture was evaporated in vacuo. The residue becomes direct continued to be used.

b) 1,2-Dimethyl-5 (6) - (5-methyl-3-oxo-4,5-dihydro-2H-6-pyridazinyl) -benzimidazole Manufactured analogously to Example 1d from the product obtained under 10a.

Yield: 0.15 g (27.4% of theory), melting point: above 2500C.

Example 11 2- (2-Fluoro-phenyl) -5 (6) - (5-methyl-3-oxo-4,5-dihydro-2H-6-pyridazinyl) benzimidazole hydrochloride 3.2 g of 5-methyl-6- / 3-amino-4- (2-fluoro-benzoylamino) -phenyl / -3-oxo-4,5-dihydro-2H-pyridazine are suspended in 150 ml of isopropanol and reflux into the mixture Hydrochloric acid gas introduced for 2 hours. It is then concentrated and the residue through Trituration with ether crystallizes.

Yield: 1.35 g (40% theoretical), melting point: 29500.

Example 12 2-Phenyl-5 (6) - (5-methyl-3-oxo-4,5-dihydro-2H-6-pyridazinyl) -benzimidazole hydrochloride Prepared analogously to Example 11 from 2.0 g of 5-methyl-6- (3-amino-4-benzoylamino-phenyl) -3-oxo-4,5-dihydro-2H-pyridazine.

Yield: 0.85 g (40.5% of theory), melting point: 3350C Example 13 2-Isopropyl-5 (6) - (5-methyl-3-oxo-4,5-dihydro-2H-6-pyridazinyl) -benzimidazole hydrochloride Prepared analogously to Example 11 from 6.2 g of 5-methyl-6- (3-amino-4-isobutyrylamino-phenyl) -3-oxo-4,5-dihydro-2H-pyridazine.

Yield: 4.7 g (71% of theory), melting point: 270-2720C.

Example 14 2-n-Pentyl-5 (6) - (5-methyl-3-oxo-4,5-dihydro-2H-6-pyridazinyl) -benzimidazole hydrochloride Prepared analogously to Example 11 from 1.8 g of 5-methyl-6- (3-amino-4-caproylamino-phenyl) -3-oxo-4,5-dihydro-2H-pyridazine.

Yield: 0.8 g (41.8% of theory), melting point: 2440C.

Example 15 2- (4-chloro-phenyl) -5 (6) - (5-methyl-3-oxo-4,5-dihydro-2H-6-pyridazinyl) -benzimidazole Prepared analogously to Example 2b from 1.45 g of 2- (4-chloro-phenyl) -5 (6) - (1 -oxo-2-methyl-3-methoxycarbonyl-1-propyl) -benzimidazole hydrochloride.

Yield: 0.32 g (23% of theory), melting point: sinters from 780C.

Example 16 2-Trifluoromethyl-5 (6) - (5-methyl-3-oxo-4,5-dihydro-2H-6-pyridazinyl) -benzimidazole 11 g of 5-methyl-6- (3,4-diamino-phenyl) -3-oxo-4,5-dihydro-2H-pyridazine are refluxed with 70 ml of trifluoroacetic acid for 2 hours. After that, will brought to dryness in vacuo, mixed with ice water and made ammoniacal. The mixture is extracted with ethyl acetate, the ethyl acetate phases are evaporated and the residue recrystallized from 50% ethanol with the addition of activated charcoal.

Yield: 6.4 g (50% of theory), melting point: 278-280 ° C.

Example 17 2-Trifluoromethyl-5 (6) - (5-methyl-3-oxo-2H-6-pyridazinyl) -benzimidazole Prepared analogously to Example 4 from 6 g of 2-trifluoromethyl-5 (6) - (5-methyl-3-oxo-4, 5-dihydro-2H-6-pyridazinyl) benzimidazole.

Yield: 0.8 g (13.5% of theory), melting point: over 3000C (from Ethanol) Example 18 5 (6) - (5-Methyl-3-oxo-4,5-dihydro-2H-6-pyridazinyl) -benzimidazole hydrochloride Prepared analogously to Example 16 from 2.0 g of 5-methyl-6- (3,4-diaminophenyl) -3-oxo-4,5-dihydro-2P-pyridazine and formic acid.

The hydrochloride is precipitated from methanol with ethereal hydrochloric acid and recrystallized from ethanol / ether.

Yield: 0.6 g (28.9% of theory), melting point: 300 ° C. (decomposition).

Example 19 2-Mercapto-5 (6) - (5-methyl-3-oxo-4,5-dihydro-2H-6-pyridazinyl) -benzimidazole 5.2 g of potassium hydroxide are in a mixture of 50 ml of ethanol and 6.6 mol of water dissolved, then 3.84 g of carbon disulfide and 11.0 g of 5-methyl-6- (3,4-diamino-phenyl) -3-oxo-4,5-dihydro-2H-pyridazine added and heated to reflux for 3 hours. It is diluted with water, with glacial acetic acid neutralized and the precipitated product filtered off with suction and washed with water.

Yield: 10.6 g of crude product (94.3% of theory). The product is Purified on a silica gel column (eluent: chloroform / ethanol = 9: 1).

Melting point: over 3000C.

Example 20 2-Methylmercapto-5 (6) - (5-methyl-3-oxo-4,5-dihydro-2H-6-pyridazinyl) -benzimidazole 6.0 g of the crude product prepared in Example 19 are dissolved in 250 ml of dimethylformamide dissolved and then 3.3 g of methyl iodide and 1.4 g of sodium bicarbonate were added. The mixture is stirred at room temperature for 1 hour and at 50 ° C. for 1 hour.

The solvent is evaporated off in vacuo, the residue with water triturated and purified over a silica gel column.

Yield: 1.5 g (23.8 t of theory), melting point: 268 ° C. (decomposition).

Example 21 2-CycloheXyl-5 (6) - (5-methyl-3-oxo-4,5-dihydro-2H-6-pyridazinyl) benzimidazole hydrochloride Prepared analogously to Example 1c and 1d from 9.7 g of 5-methyl-6- (3-nitro-4-cyclohexylcarbonylamino-phenyl) -3-oxo-4,5-dihydro-2H-pyridazine. The hydrochloride is made from acetone with ethereal Hydrochloric acid precipitated and recrystallized from ethanol.

Yield: 2.3 g (24.7% of theory) Melting point: 315-320 ° C. Example 22 2- (4-tert-Butyl-phenyl) -5 (6) - (5-methyl-3-oxo-4,5-dihydro-2H-6-pyridazinyl) -benzimidazole hydrochloride hydrate a) 5-Methyl-6- / 3-amino-4- (4-tert-butyl-benzoyl-amino) -phenyl / -3-oxo-4,5-dihydro-2H-pyridazine Prepared analogously to Example 1c from 12.6 g of 5-methyl-6- / 3-nitro -4- (4-tert-Butyl-benzoyl-amino) -phenyl7-3-oxo-4,5-dihydro-2H-pyridazine. After this Filtering off the catalyst, the product is precipitated with water.

Yield: 9.9 g (84.5% of theory) Melting point: 215-2170C b) 2- (4-tert-Butyl-phenyl-5 (6) - (5-methyl-3-oxo-4,5-dihydro-2H-6-pyridazinyl) benzimidazole hydrochloride hydrate Manufactured analogously to Example 1d from the product obtained under a).

Yield: 7.9 g (73% of theory). Melting point: 294-298 ° C.

Example 23 2- (2-Pentyl-5 (6) - (5-methyl-3-oxo-4,5-dihydro-2H-6-pyridazinyl) -benzimidazole hydrochloride a) 5-Methyl-6-t3-amino-4- (2-methyl-valeryl-alr.ino) -phenyl-3-oxo-4,5-dihydro-2H-pyridazine Prepared analogously to Example 22a) from 12.5 g of 5-methyl-6-t3-nitro-4- (2-methyl-valeryl-amino) pheny-3-oxo-4,5-dihydro-2H-pyridazine. After adding water, the product becomes extracted with ethyl acetate.

Yield: 4.2 g (36.6% of theory). Melting point: 179-1810C.

b) 2- (2-pentyl) -5 (6) - (5-methyl-3-oxo-4,5-dihydro-2H-6-pyridazinyl-benzimidazole) Hydrochloride Prepared analogously to Example 1d from the product obtained under a).

Yield: 1.3 g (28.4% of theory). Melting point: sinters from 1500C.

Example 24 2- (n-HeXyl) -5 (6) - (5-methyl-3-oxo-4,5-d-Hydro-2H-6-pyridazinyl) -benzimidazole hydrochloride a) 5-Methyl-6- (3-amino-4-heptanoyl-aminophenyl) -3-oxo-4,5-dihydro-2Y.-pyridazine Prepared analogously to Example 22a) from 11.75 g of 5-methyl-6- (3-nitro-4-heptanoyl-aminophenyl) -3-oxo-4,5-dihydro-2H-pyridazine.

Yield: 8.0 g (78% of theory). Melting point: 158-1600C.

b) 2- (n-Hexyl) -5 (6) - (5-methyl-3-oxo-4,5-dihydro-2H-6-pyridazinyl) -benzimidazole hydrochloride Manufactured analogously to Example 1d from the product obtained under a).

Yield: 6.2 g (73.5% of theory), melting point: 225-2270C.

Example 25 1-CycloheXyl-2-methyl-5 (6) - (5-methyl-3-oxo-4,5-dihydro-2H-6-pyridazinyl) -benzimidazole 1.3 g of 5-methyl-6- (3-amino-4-cyclohexylamino-phenyl) -3-oxo-4,5-dihydro-211-pyridazine are refluxed with 50 ml of glacial acetic acid for 6 hours. The reaction mixture is Poured onto ice, neutralized with ammonia and the precipitated product over a Purified silica gel column (eluent: methylene chloride / acetone = 10: 0 to 9: 1).

Yield: 0.4 g (28.5% of theory), melting point: 259-2620C (decomposition) Example 26 5 (6) - (5-Methyl-3-oxo-4,5-dihydro-2H-6-pyridazinyl) -benzimidazol) -2-one 2 g of 2-methylmercapto-5 (6) - (5-methyl-3-oxo-4,5-dihydro-2H-6-pyridazinyl) benzimidazole are dissolved in 100 ml of glacial acetic acid, and 10 ml of 30% hydrogen peroxide are added and heated to 50 ° C for 6 hours. After 3 and 4 hours, 2 ml of hydrogen peroxide are added each time yielded. The reaction mixture is largely concentrated in vacuo, on water poured and the precipitate recrystallized from ethanol / cyclohexane.

Yield: 0.37 g (21% of theory), melting point: over 3000C.

Example 27 2- (2-Methoxy-4-methylmercapto-phenyl) -5 (6) - (5-methyl-3-oXo-4, 5-dihvdro-2H-6-pyridazinyl) -benzimidazole 2.5 g 5-methyl-6-z3-amino-4- (2-methoxy-4-methylmercapto-benzoylamino) -phenyl2-3-oxo-4,5- dihydro-2H-pyridazine are refluxed in 100 ml of glacial acetic acid for 2.5 hours, the reaction mixture filtered hot and, after cooling, poured into a mixture of ice and concentrated Stir in ammonia. The precipitated product is dried from methylene chloride recrystallized.

Yield: 1.1 g (57.7 e of theory), melting point: 155-1650C (decomposition).

Example 28 1-Cyclopropyl-2-methyl-5 (6) - (5-methyl-3-oxo-4,5-dihydro-2H-6-pyridazinyl) -benzimidazole a) 5-methyl-6- (3-amino-4-cyclopropylamino-phenyl) -3-oxo-4,5-dihydro-2H-pyridazine 5.8 g of 5-methyl-6- (3-nitro-4-cyclopropylamino-phenyl) -3-oxo-4,5-dihydro-2H-pyridazine are in a mixture of 100 ml of ethanol and 20 ml of glacial acetic acid in the presence of 0.5 g of 10% palladium-carbon is hydrogenated with hydrogen of 5 atm. It will be 120 ml of glacial acetic acid was added, the catalyst was filtered off and the filtrate was evaporated in vacuo. The residue is reacted further without further purification.

b) 1-Cyclopropyl-2-methyl-5 (6) - (5-methyl-3-oxo-4,5-dihydro-2H-6-pyridazinyl) -benzimidazole Prepared analogously to Example 25 from the product obtained under a) and 30 ml glacial acetic acid (heating time: 3 hours, column cleaning not required).

Yield: 4.6 g (81.5% of theory), melting point: 246-2500C.

Example 29 2-HeXylmercapto-5 (6) - (5-methyl-3-oxo-4,5-dihydro-2H-6-pyridazinyl) -benzimidazole Prepared analogously to Example 20 from 2.6 g of 2-mercapto-5- (6) - (5-methyl-3-oxo-4,5-dihydro-2H-6-pyridazinyl) benzimidazole and 1.7 g of 1-bromohexane (reaction temperature: 80 ° C., reaction time: 7 hours).

Yield: 1.0 g (29% of theory), melting point: 172 ° C. (decomposition, from isopropanol / petroleum ether) Example A tablets of 100 mg 2- (4-Methoxyphenyl) -5 (6) - (5-methyl-3-oxo-4,5-dihydro-2H-6-pyridazinyl) -benzimidazole hydrochloride Composition: 1 tablet contains: active substance 100.0 mg lactose 50.0 mg polyvinylpyrrolidone 5.0 mg carboxymethyl cellulose 19.0 mg magnesium stearate 1.0 mg 175.0 mg active ingredient and moisten milk sugar evenly with an aqueous solution of polyvinylpyrrolidone.

Wet sieving: 1.5 mm Drying: t Circulating air drying cabinet 500C Drying sieves: 1 mm Mix the remaining excipients with the granulate and final mix to tablets press.

Tablet weight: 175 mg Punch: 8 mm Example B coated tablets of 50 mg 2- (4-Methoxyphenyl) -5 (6) - (5-methyl-3-oxo-4,5-dihydro-2H-6-pyridazinyl) -benzimidazole-hydrochloride 1 tablet core contains: Active ingredient 50.0 mg corn starch sep. 20.0 mg Soluble Starch 2.0 mg carboxymethyl cellulose 7.0 mg magnesium stearate 1.0 mg 80.0 mg Active ingredient and moisten starch with aqueous solution of soluble starch evenly.

Wet sieving: 1.0 mm Dry sieving: 1.0 mm Drying: 500C in a circulating air drying cabinet Mix the granulate and the remaining auxiliary materials and press into cores.

Core weight: 80 mg Punch: 6 mm Radius of curvature: 5 mm The finished The cores are coated in sugar in the usual way in a coating pan.

Drage weight: 120 mg Example C suppositories of 75 mg 2- (4-methoxyphenyl) -5 (6) - (5-methyl-3-oxo-4,5-dihydro-2H-6-pyridazinyl) benzimidazole hydrochloride 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 Manufacturing process: The suppository mass is melted. At 38 ° C., the ground active substance is homogeneously dispersed in the melt. It is cooled to 350C and poured into pre-cooled suppository molds.

Suppository weight: 1.7 g Example D ampoules of 50 mg 2- (4-methoxyphenyl) -5 (6) - (5-methyl-3-oxo-4, 5-dihydro-2H-6-pyridazinyl) -benzimidazole hydrochloride 1 ampoule contains: active substance 50.0 mg sorbitol 250.0 mg dist. water ad 5.0 ml Manufacturing process: The active substance and sorbitol are in least Dissolved water, then it is made up to the specified volume and sterile-filtered.

Filling: in ampoules of 5 ml. Sterilization: 20 minutes at 1200C Example E Drops of 25 mg per 5 ml of 2- (4-methoxyphenyl) -5 (6) - (5-methyl-3-oxo-4 , 5-dihydro-2H-6-pyridazinyl) benzimidazole hydrochloride active substance 5.0 g p-oxybenzoic acid methyl ester 0.035 g propyl p-oxybenzoate 0.015 g anise oil 0.05 g menthol 0.06 g sodium saccharin 1.0 g glycerine 10.0 g ethanol 40.0 g distilled water to 100.0 ml Production method: The benzoic acid esters are dissolved in ethanol and then the aniseed oil and the Menthol added. Then the active ingredient, glycerin and saccharin sodium in Added dissolved water. The solution is then filtered clear.

Claims (14)

New benzimidazoles and their use Patent claims: 1. New benzimidazoles of the general formula in which AA and B each have a hydrogen atom or a further bond together, R1 is a hydrogen atom, the trifluoromethyl group, an alkyl group with 1 to 6 carbon atoms, a cycloalkyl group with 3 to 7 carbon atoms, a hydroxyl group optionally substituted by an alkyl group with 1 to 6 carbon atoms or a mercapto group or a phenyl group which can be mono-, di- or trisubstituted by a halogen atom, an alkyl group having 1 to 4 carbon atoms and / or a hydroxyl or mercapto group optionally substituted by an alkyl group having 1 to 3 carbon atoms, the substituents des Phenyl nuclei can be the same or different, R2 is a hydrogen atom, an alkyl group with 1 to 3 carbon atoms or a cycloalkyl group with 3 to 6 carbon atoms and R3 is an alkyl group with 1 to 6 carbon atoms, their optically active antipodes if A and B each represent a hydrogen atom, their 1 H and 3 H tautomers and their physiolog isch compatible acid addition salts with inorganic or organic acids. 2. New benzimidazoles according to claim 1, characterized in that in the general formula I A and B each have a hydrogen atom or together another one Bond, R1 a hydrogen atom, the trifluoromethyl group, an alkyl group with 1 to 6 carbon atoms, a cycloalkyl group with 3 to 7 carbon atoms, one optionally substituted by an alkyl group having 1 to 6 carbon atoms Hydroxy or mercapto group or a phenyl group, which is replaced by a halogen atom, an alkyl group with 1 to 4 carbon atoms, a hydroxy, methoxy, mercapto or methyl mercapto group can be mono- or disubstituted, the substituents of the phenyl nucleus can be identical or different, R2 is a hydrogen atom, the Methyl group or a cycloalkyl group having 3 to 6 carbon atoms and R3 is one Denote an alkyl group with 1 to 4 carbon atoms, their optically active antipodes, if A and B each represent a hydrogen atom, and their physiologically compatible Acid addition salts with inorganic or organic acids. 3. New benzimidazoles according to claim 1, characterized in that in the general formula I A and B each have a hydrogen atom or together another one Bond, R1 is a hydrogen atom, the methyl, isopropyl, cyclopropyl, cyclohexyl, n-hexyl, 1-pentyl, 2-pentyl, hydroxy, methyl mercapto, exyl mercapto, trifluoromethyl, 2-fluorophenyl, 2,4-difluorophenyl, 2-methoxyphenyl, 4-methoxyphenyl, 2,4-dimethoxyphenyl, 3,4-dimethoxyphenyl, 2-methyl mercaptophenyl, 4-methyl mercaptophenyl, 2,4-dimethyl mercaptophenyl, 2-methoxy-4-methylmercaptophenyl-, 2-methoxy-5-methylmercaptophenyl-, 4-tert-butylphenyl- or 2-methylmercapto-4-methoxyphenyl group, R2 is a hydrogen atom, the methyl, Cyclopropyl or cyclohexyl group and R3 denotes the methyl group, their optical active antipodes when A and B each represent a hydrogen atom, and their physiological compatible acid addition salts with inorganic or organic acids. 4. 2-Ftethyl-5 (6) - (5-methyl-3-oxo-4,5-dihydro-2H-6-pyridazinyl) benzimidazole, its optically active antipodes and acid addition salts. 5. 2- (4-methoxyphenyl) -5 (6) - (5-methyl-3-oxo-4,5-dihydro-2H-6-pyridazinyl) benzimidazole, its optically active antipodes and acid addition salts. 6. 2- (4-Methyl-phenyl) -5 (6) - (5-methyl-3-oxo-4,5-dihydro-6-pyridazinyl) -benzimidazole, its optically active antipodes and acid addition salts. 7. 2-methylmercapto-5 (6) - (5-methyl-3-oxo-4, 5-dihydro-2H-6-pyridazinyl) benzimidazole, its optically active antipodes and acid addition salts. 8. Use of the new benzimidazoles according to claim 1 for combating of cardiovascular diseases. 9. Medicament containing a compound according to claim 1 in addition to one or more inert carriers and / or diluents. 10. Process for the preparation of new benzimidazoles of the general formula in which A and B each have a hydrogen atom or together a further bond, R1 a hydrogen atom, the trifluoromethyl group, an alkyl group with 1 to 6 carbon atoms, a cycloalkyl group with 3 to 7 carbon atoms, a hydroxy optionally substituted by an alkyl group with 1 to 6 carbon atoms or a mercapto group or a phenyl group which can be mono-, di- or trisubstituted by a halogen atom, an alkyl group having 1 to 4 carbon atoms and / or a hydroxyl or mercapto group optionally substituted by an alkyl group having 1 to 3 carbon atoms, the substituents des Phenyl nucleus can be the same or different, R2 is a hydrogen atom, an alkyl group with 1 to 3 carbon atoms or a cycloalkyl group with 3 to 6 carbon atoms and R3 is an alkyl group with 1 to 6 carbon atoms, as well as their optically active antipodes, if A and B each represent a Represent hydrogen atom, of which 1 H and 3 H are tautomers and of their physiologically tolerable acid addition salts with inorganic or organic acids, characterized in that a) a compound of the general formula, optionally prepared in the reaction mixture in which A, B, R2 and R3 are as defined at the outset, one of the radicals X or Y is a hydrogen atom and the other of the radicals X or Y is a group of the formula represents, in which Z1 and Z2, which may be the same or different, optionally substituted by lower alkyl groups, hydroxy or mercapto groups or Z1 and Z2 together an oxygen or sulfur atom, an imino group optionally substituted by an alkyl group having 1 to 3 carbon atoms, an alkylenedioxy - Or alkylenedithio group each having 2 or 3 carbon atoms and R4 has the meanings mentioned for R1 at the beginning or represents an amino group optionally substituted by an alkyl group having 1 to 3 carbon atoms, or its alkali metal salts, if R4 represents the mercapto group, is cyclized or b) a carboxylic acid the general formula in which A, B and RX to R3 are as defined at the outset, or their esters, amides or halides are reacted with hydrazine and, if desired, then a compound of general formula I obtained according to process a or b, in which A and B each have a hydrogen atom represents, is converted by means of dehydration into a compound of the general formula I in which A and B together represent a further bond and / or a compound of the general formula I obtained in which R1 is the hydroxyl or mercapto group or a phenyl group which is represented by a hydroxy and / or mercapto group is mono-, di- or trisubstituted, and / or R2 represents a hydrogen atom, is converted into a corresponding alkoxy, alkylmercapto and / or alkyl compound of the general formula I by means of alkylation and / or a compound obtained of the general formula I, in which R1 represents an alkyl mercapto group, by means of oxidation and subsequent hydrolytic cleavage of the A formed Alkylsulfinyl or alkylsulfonyl group is converted into a corresponding hydroxy compound of the general formula I and / or a resulting racemic mixture of a compound of the general formula I is split into its optically active antipodes by means of racemate resolution and / or a obtained compound of the general formula I into its physiological compatible acid addition salts is converted with inorganic or organic acids. 11. The method according to claim 10a, characterized in that the Reaction carried out in a solvent and at temperatures between 0 and 2500C will. 12. The method according to claim 10a and 11, characterized in that the cyclization in the presence of a condensing agent or in the presence of a Base is carried out. 13. The method according to claim 10b, characterized in that die'Uetzung Reaction carried out in a solvent at temperatures between 0 and 150 ° C will. 14. The method according to claim 1Ob and 13, characterized in that the reaction is carried out in the presence of an acidic condensing agent.