CH617428A5 - Process for the preparation of novel 1-sulphonyl- benzimidazoles - Google Patents

Description

The invention relates to a process for the preparation of new 1-sulfonylbenzimidazoles which are interesting antiviral agents.

Viruses in the upper respiratory tract are quite high. It is estimated that there are nearly 1 trillion such cases in the United States annually. Studies in England (Tyrell and Bynoe, 1966) showed that 74% of people with colds were infected with rhinoviruses. After over 80 strains of rhinoviruses have been identified, the development of a reasonable rhinovirus vaccine is not possible. One seems to be able to counter this disease with chemotherapy.

The ability of chemical compounds to suppress the growth of viruses in vitro can easily be demonstrated by a viral leaflet suppression test which is similar to the test described by Siminoff in Applied Microbiology 9 (1), 66 (1961).

The object of the invention is therefore to create new sulfonylbenzimidazoles which allow the growth of certain viruses, including 25 strains of rhinoviruses, polio (types I, II, III), coxsackie (A9, A21, B5), echovirus (strains 1, 2 , 3, 4) and inhibit mengovirus. It is known that the rhinovirus s

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occur along with the common cold. The compounds produced according to the invention are potentially suitable for the treatment of such viral infections in warm-blooded animals and in humans.

Certain 1-dimethylaminosulfonyl-2-aminobenzimidazoles are known from DT-OS 2 206 010 and US Pat. No. 3,853,908; the compounds described there are fungicides.

The invention is now based on a process for the preparation of new pharmacologically active 1-sulfonylbenzimidazoles of the formula I.

R.

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directed in what

Ri for Ci-C5-alkyl, methylcyclopropyl, methylcyclohexyl, C3-C7-cycloalkyl, phenyl, furyl, thienyl, thiazole- 25

2-yl, 2-acetamido-4-methylthiazol-5-yl, 1,3,4-thiadiazol-2-yl, 2-methyl-l, 3,4-thiadiazol-5-yl, 2-methyl amino-l, 3,4-thiadiazol-5-yl or R4R5N-, where the substituents R4 and Rs independently of one another are C1-C3-alkyl or together with the nitrogen atom to which they are bound 30 are pyrrolidino, piperidino or morpholino ,

R2 is hydrogen, methyl, amino, acetamido or methylamino,

R3 for Ci-Cs-alkoxycarbonyl, allyloxycarbonyl, Pro 35

pargyloxycarbonyl, (C3-C7-cycloalkyl) oxycarbonyl, (C3-C7-cycloalkyl) methyloxycarbonyl, l- (C3-C7-cyclo-alkyl) ethyloxycarbonyl, benzyloxycarbonyl, alpha-methylbenzyloxycarbonyl, phenoxycarbonyl, Ci-Cs-Alkoxycar-bonylmethyl, l - (Ci-Cs-Alkoxycarbonyl) ethyl, hydra- 40

zinocarbonyl, carboxy, carboxamido, N- (Ci-C4-alkyl) -carboxamido, N- (Ci-C4-alkoxy) carboxamido, hydroxymeth-yl, cyano, methylsulfonyl or trifluoromethyl and the substituent R3 is in position 5 or 6 , which is characterized in that a tautomeric 45th

Benzimidazole of the formula II

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II

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with a sulfonyl chloride of the formula R1SO2CI, in which the substituents R 1, R 2 and R 3 have the meanings given above.

Tautomeric benzimidazole is understood to mean a benzimidazole which can be substituted on one of the two nitrogen atoms by a hydrogen atom. The benzimidazole unsubstituted on nitrogen, which is substituted in position 5 of the benzene radical, has a corresponding tautomeric form, in which the substituent is also alternately in position 6. The isomeric mixture can be specified by numbering the alternating positions by 5 (6). As a result of such a tautomerism, one gets one in the implementation

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5 (6) -substituted benzimidazole with a sulfonyl chloride isomer mixture of 5 (6) -substituted sulfonylbenz-imidazoles.

The various general substituents used above are described below. The statement furyl refers to a furan residue bound via position 2 or position 3. Thienyl is understood to mean the thiophene radical which is bonded via position 2 or 3. The statement thiazol-2-yl or 2-thiazoI refers to the thiazole radical bonded via position 2. 1,3,4-Thiadiazol-2-yl or simplified thiadiazol-2-yl is understood to mean the 1,3,4-thiadiazole radical bonded via position 2. The statement 2-methyl-l, 3,4-thiadiazol-5-yl or 2-methylamino-l, 3,4-thia-diazol-5-yl refers to a correspondingly 2-substituted 1 bonded via position 5 , 3,4-thiadiazole residue.

As Ci-Cs-alkyl straight-chain or branched aliphatic radicals with 1 to 8 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl,

Isobutyl, sec.-butyl, tert.-butyl, amyl, isoamyl,

sec.-amyl, sec.-isoamyl (1,2-dimethylpropyl),

tert-amyl (1,1-dimethylpropyl), neopentyl, hexyl,

Isohexyl (4-methylpentyl), sec-hexyl (1-methylpentyl), 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl,

2,2-dimethylbutyl, 3,3-dimethylbutyl, 1,2-dimethylbutyl,

1,3-dimethylbutyl, 1,2,2-trimethylpropyl, 1,1,2-tri-methylpropyl, heptyl, isoheptyl (5-methylhexyl),

sec-heptyl (1 methylhexyl), 2,2-dimethylpentyl, 3,3-dimethylpentyl, 4,4-dimethylpentyl, 1,2-dimethylpentyl, 1,3-dimethylpentyl, 1,4-dimethylpentyl, 1,2 , 3-trimethylbutyl, 1,1,2-trimethylbutyl, 1,1,3-tri-methylbutyl, octyl, isooctyl (6-methylheptyl), sec.-octyl (1-methylheptyl) or tert.-octyl (1.1 , 3,3-tetra-methylbutyl). Ci-Cs-alkylcarbinol refers to straight-chain or branched aliphatic alcohols with 1 to 8 carbon atoms, the ethyl radicals of which are exemplified by the above information. Ci-Cs-alkoxy means, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec.-butoxy, amyloxy, isoamyloxy, 1,2-dimethylpropoxy, tert.-amyl-oxy, neoptentyloxy, hexyloxy, (2-methyl- l-pentyl) oxy, (4-methyl-2-pentyl) oxy, (2-ethyl-l-butyl) oxy, heptyl-oxy, 2-heptyloxy, octyloxy, 2-octyloxy, (2-ethylhexyl) -oxy, Isooctyloxy or (2,2,4-trimethyl-l-pentyl) oxy.

C3-C7-cycloalkyl is understood to mean the saturated alicyclic rings with 3 to 7 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. Methylcyclohexyl can be 1-, 2-, 3- or 4-methylcyclohexyl. C3-C7-cycloalkylmethyl refers to methyl substituted by saturated alicyclic rings with 3 to 7 carbon atoms, such as cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl or cyclohept-tylmethyl. C3-C7-cycloalkyl alcohol means, for example, cyclopropanol, cyclobutanol, cyclopentanol, cyclohexanol or cycloheptanol.

The C 1 -C 4 -alkylamines mentioned below are understood to mean aliphatic amines having 1 to 4 carbon atoms, such as methylamine, ethylamine, propylamine, isopropylamine, butylamine or sec-butylamine. C1-C4-alkoxyamine refers, for example, to methoxyamine, ethoxyamine, propoxyamine, isopropoxyamine or butoxyamine.

The starting products are benzimidazoles with the indicated substituents in position 5 (6). The benzimidazole and the sulfonyl chloride are normally used in approximately equimolar amounts, but it is also possible, if desired, to work with an excess of one of the two reactants without adversely affecting the yield of the product. The reaction can be carried out in a number of known non-reactive solvents, for example

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as in acetone, tetrahydrofuran (THF), tertiary amides such as N, N-dimethylformamide (DMF), and in chlorinated hydrocarbons such as dichloromethane, dichloroethane and chloroform. A base which serves as an acid binder can also be added to the reaction medium. Examples of suitable bases here are pyridine, triethylamine, N-methylmorpholine, sodium bicarbonate and sodium hydride. A preferred solvent medium for the reaction is acetone, which contains triethylamine, or tetrahydrofuran with dimethylformamide, which contains sodium hydride as the base.

The reaction is best carried out at temperatures between room temperature and the reflux temperature of the respective solvent system. The process is preferably carried out at the reflux temperature, and at this temperature the reaction is essentially complete within 1 to 48 hours.

The reaction product obtained is 1-sulfonylbenzimidazole, which is hereinafter simply referred to as sulfonylbenzimidazole. The product can be isolated by filtering the reaction mixture and concentrating the filtrate to initiate crystallization. Alternatively, the reaction mixture can be evaporated to dryness and the residue treated with a suitable solvent, such as acetone or methanol, in order to separate and remove any insoluble material present in this way. To crystallize the product, the solution containing the sulfonylbenzimidazole is either concentrated or evaporated to give a second residue which is then dissolved, for example, in methanol. The desired sulfonylbenzimidazole can be obtained from the methanol solution by crystallization.

The reaction of the tautomeric benzimidazole and the sulfonyl chloride generally leads to a 1: 1 mixture of the 5- and 6-substituted sulfonylbenzimidazole isomers. The isomers can be separated from one another by fractional crystallization or by column chromatography. Usually the 6-isomer crystallizes out of a solution of the mixture first. If, for example, ethyl 2-amino-5-benzimidazole carboxylate is reacted with dimethylsulfamoylchloride in acetone containing triethylamine, then ethyl 1-dimethylaminosulfonyl-2-amino-6-benzimidazole carboxylate first crystallizes out of the reaction mixture. The acetone mother liquors predominantly contain ethyl l-dimethylaminosulfon-yl-2-amino-5-benzimidazole carboxylate and residual amounts of 6-isomer. The isomers can be identified by their nuclear magnetic resonance spectra in the range of the phenyl proton (7.0 to 8.3 ppm).

Some of the compounds of formula I can also be prepared by acetylating, hydrolyzing or reducing the corresponding sulfonyl-benzimidazole precursors. If the reactions are carried out with compounds which are an isomeric mixture of the sulfonylbenzimidazoles, the isomeric products obtained can be separated from one another, for example by fractional crystallization or by chromatography.

The 2-acetamidosulfonylbenzimidazoles can e.g. B. can also be prepared by subsequent acetylation of the corresponding 2-aminosulfonylbenzimidazole with acetic anhydride. Stirring a mixture of ethyl 1-dimethylaminosulfonyl-2-amino-5 (6) -benzimidazole carboxylate isomer with acetic anhydride at room temperature gives, for example, ethyl-1-dimethylaminosulfonyl-2-aceta-mido-5 (6) -benzimidazole carboxylate in the form of a mixture. The isomeric 2-acetamidosulfonylbenzimidazoles can be separated from one another by fractional crystallization from acetone or preferably from methanol or ethanol.

Mixtures of isomeric sulfonylbenzimidazole esters can be separated from one another by selective hydrolysis of the more labile ester groups. A mixture of the ethyl-1-diethylaminosulfonyl-2-amino-5 (6) -benzimidazole carboxylate isomers can be hydrolyzed, for example, in aqueous potassium hydroxide. The insoluble, unreacted 6-isomer is separated off by filtration. The basic aqueous filtrate mainly contains potassium l-diethylaminosulfonyl-2-amino-5-benzimidazole carboxylate and a small amount of the 6-isomer salt. The filtrate is neutralized with dilute acid, whereupon l-diethylaminosulfonyl-2-amino-5-benzimidazole carboxylic acid precipitates and is obtained. The sulfonylbenzimidazolecarboxylic acids can be converted into their esters in a manner known per se by reaction with thionyl chloride in the presence of a Ci-Cs-carbinol solvent or by other esterification processes. Ester hydrolyzates which have amino groups in position 2 should be precipitated in the pH range from 0.5 to 7.0.

Esters that are not ethyl esters of 5 (6) sulfonylbenzimidazole carboxylic acids can be reacted with the molar equivalents of a Ci-Cs-alkylcarbinol, a C3-C7-cycloalkyl alcohol, a C3-C7-cycloalkylmethanol by reacting the corresponding 5 (6) -sulfonylbenzimidazole carboxylic acids , a 1- (0-C7-cycloalkyl) ethanol, allyl alcohol, propargyl alcohol, benzyl alcohol, alpha-methylbenzyl alcohol or phenol with 1,1-carbonyldiimidazole in the presence of a trace of a carbonyl anion. Preferred esters can be prepared by reacting the corresponding sulfonylbenzimidocarboxylic acid with propanol, isopropanol, neopentyl alcohol, cyclobutanol, cyclohexanol or 1- (cyclopropyl) ethanol (alpha-methylcyclopropanemethanol) in the presence of 1,1-carbonyldiimidazole in the above manner. The sulfonylbenzimidazole carboxylic acids required for this can be prepared from the corresponding ethyl ester precursors by basic hydrolysis. The N-substituted sulfonylbenzimidazolecarboxamides can be prepared in a similar manner by reacting the same sulfonylbenzimidazolecarboxylic acids with molar equivalents of a Ci-Ci-alkylamine or a Ci-Ci-alkoxyamine and with l, l'-carbonyldiimidazole in dimethylformamide. If the corresponding 2-acetamidosulfonylbenzimidazole carboxylic acid is used as the starting product, the desired 2-amino ester or the desired 2-amide can be prepared by basic hydrolysis of the 2-acetyl group after esterification or amidation. For example, by reacting 1-dimethylaminosulfonyl-2-acetamido-5 (6) -benzimidazolecarboxylic acid with one equivalent of isopropylamine or methoxyamine and 1,1-carbonyldiimidazole in dimethylformamide as products 1-dimethylaminosulfonyl-2-acetamido-5 (6 ) -N-isopropylbenzimidazolecarboxamide or l-dimethylaminosulfonyl-2-aceta-mido-5 (6) -N-methoxybenzimidazolecarboxamide. Primary amides can be obtained if a 5 (6) -sulfonylbenzimidazole carboxylic acid is reacted with ammonia and 1,1'-carbonyldiimidazole.

Examples of esters and amides of the sulfonylbenzimidazolecarboxylic acids of the formula I are as follows:

1-cyclopropylsulfonyl-2-methyl-5 (6) -benzimidazole-

carboxylic acid cyclopropyl ester,

1- (2-furan) sulfonyl-2-amino-5 (6) -benzimidazole-

carboxylic acid cyclopentyl ester,

1 - (2-thiophene) sulfonyl-2-methylamino-5 (6) -benz-

cyclohexyl imidazole carboxylic acid,

1- (2-thiazole) sulfonyl-2-acetamido-5 (6) -benzimidazole-

carboxylic acid cycloheptyl ester l-cyclopentylsulfonyl-2-amino-5 (6) -benzimidazole-

carboxylic acid cyclopropyl methyl ester l- [2- (l, 3,4-thiadiazole) sulfonyl] -2-amino-5 (6) -

benzimidazole carboxylic acid cyclobutyl methyl ester,

l-cyclohexylsulfonyl-2-methylamino-5 (6) -benzimidazole-

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carboxylic acid cyclopentyl methyl ester,

l-isopropylsulfonyl-2-amino-5 (6) -benzimidazolecarbon-

acid cycloheptyl methyl ester,

1-dimethylaminosulfonyl-2-amino-5 (6) -benzimidazole-

carboxylic acid 1 - (cyclopropyl) ethyl ester,

l-piperidinosulfonyl-2-acetamido-5 (6) -benzimidazole-

carboxylic acid l- (cyclobutyl) ethyl ester,

l-pyrrolidinosulfonyl-2-amino-5 (6) -benzimidazole-

carboxylic acid l- (cyclopentyl) ethyl ester,

1 -diethylaminosulfonyl-2-methyl-5 (6) -benzimidazole-

carboxylic acid l- (cyclohexyl) ethyl ester,

l-dipropylaminosulfonyl-2-methyl-5 (6) -benzimidazole-

carboxylic acid 1 - (cycloheptyl) ethyl ester,

1-dimethylaminosulfonyl-2-amino-5 (6) -benzimidazole-

carboxylic acid 2-methylcyclohexyl ester,

l-diethylaminosulfonyl-2-amino-5 (6) -benzimidazole-

3-methylcyclohexyl carboxylate,

Isopropyl-l- (2-furan) ~ sulfonyl-2-acetamido-5 (6) -

benzimidazole carboxylate,

Neopentyl-l- (2-thiazole) sulfonyl-2-amino-5 (6) -

benzimidazole carboxylate,

Cyclohexyl-1- (2-acetamido-4-methylthiazol-5-yl) sulfonyl-2-methyl-5 (6) -benzimidazole carboxylate,

1- (2-methylamino-l, 3,4-thiadiazol-5-yl) sulfonyl

2-methylamino-5 (6) -benzimidazolecarboxylic acid 1- (cyclopropyl) ethyl ester,

Neopentyl-l-dimethylaminosulfonyl-2-acetamido-5 (6) -

benzimidazole carboxylate,

Isopropyl-1-isopropylsulfonyl-2-amino-5 (6) -

benzimidazole carboxylate,

Neopentyl-1-benzenesulfonyl-2-methyl-5 (6) -

benzimidazole carboxylate,

Cyclobutyl-l- (2-thiophene) sulfonyl-5 (6) -benzimidazole-carboxylate,

Cyclohexyl-1- (2-thiazoI) sulfonyl-2-amino-5 (6) -benzimidazole carboxylate,

1-dimethylaminosulfonyl-2-amino-5 (ó) -benzimidazole-carboxylic acid-l- (cyclopropyl) ethyl ester,

Neopentyl-1-dimethylaminosulfonyl-2-amino-5 (6) -benzimidazole carboxylate,

Cyclobutyl-l- (N-methyl-N-ethylaminosulfonyl) -2-amino-

5 (6) -benzimidazole carboxylate,

Isopropyl-l- (N-methyl-N-propylaminosulfonyl) -2-

acetamido-5 (6) -benzimidazole carboxylate,

Cyclohexyl-1-dipropylaminosulfonyl-2-methyl-5 (6) -

benzimidazole carboxylate,

Isopropyl-l-pyrrolidinosulfonyl-2-amino-5 (6) -

benzimidazole carboxylate,

Neopentyl-l-piperidinosulfonyl-2-acetamido-5 (6) -benzimidazole carboxylate,

Cyclobutyl-l-piperidinosulfonyl-2-methyl-5 (6) -benzimidazole carboxylate,

1-isopropylsulfonyl-2-acetamido-5 (6) -benzimidazole-

carboxylic acid 4-methylcyclohexyl ester,

l-dimethylaminosulfonyl-2-amino-5 (6) -benzimidazole-

carboxylic acid 1-methylcyclohexyl ester,

l-dimethylaminosulfonyl-2-acetamido-5 (6) -N-methyl-

benzimidazole carboxamide,

1 - (2-methyl-1,3,4-thiadiazol-5 -yl) sulfonyl-2-methyl-5 (6) -N-ethylbenzimidazole carboxamide, l-pyrrolidinosulfonyl-2-methylamino-5 (6) -N- propyl-benzimidazole carboxamide,

l-morpholinosulfonyl-2-methylamino-5 (6) -N-isopropyl-benzimidazole carboxamide,

l-dipropylaminosulfonyl-5 (6) -N-butylbenzimidazole-carboxamide,

l - [(3-furan) sulfonyl] -5 (6) -N-sec-butylbenzimidazole-carboxamide,

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l-pyrrolidinosulfony I-5 (6) -N-isobutylbenzimidazole-carboxamide,

1-phenylsulfonyl-2-amino-5 (6) -N-tert-butylbenzimidazolecarboxamide,

l-butylsulfonyl-2-acetamido-5 (6) -N-methoxybenz-imidazole carboxamide,

l-isobutylsulfonyl-2-methylamino-5 (6) -N-ethoxybenz-imidazolecarboxamide,

l-diisopropylaminosulfonyl-2-methyl-5 (6) -N-propoxy-benzimidazole carboxamide,

l-diethylaminosulfonyl-2-acetamido-5 (6) -N-isopropoxy-benzimidazole carboxamide,

l-dimethylaminosulfonyl-2-amino-5 (6) -N-butoxybenz-imidazole carboxamide,

1 -piperidinosulfonyl-5 (6) -N-isobutoxybenzimidazole-carboxamide,

l - [(2-methyl-l, 3,4-thiadiazol-5-yI) sulfonyl] -2-methyl-amino-5 (6) -N-sec-butoxybenzimidazole carboxamide and l-cyclopropylsulfonyl-2-acetamido-5 (6) -N-tert-butoxy-benzimidazole carboxamide.

The ethyl esters of sulfonylbenzimidazole carboxylic acid or the isomeric mixtures thereof can be reacted with hydrazine in a carbinyl solvent to give the corresponding hydrazides. For example, by refluxing ethyl l-dimethylaminosulfonyl-2-methyl-5 (6) -benzimidazole carboxylate with hydrazine hydrate in methanol, the l-dimethylaminosulfonyl-2-methyl-5 (6) -benzimidazole-carboxylic acid hydrazide is obtained. The hydrazides or their isomeric mixtures are suitable for the preparation of the corresponding sulfonylbenzimidazole carboxamides by cleaving the hydrazide function using Raney nickel. For example, by refluxing l-dimethylaminosulfonyl-2-methyl-5 (6) -benzimidazolecarboxylic acid hydrazide with Raney nickel in ethanol, the l-dimethylaminosulfonyl-2-methyl-5 (6) -benzimidazolecarboxamide is obtained. Corresponding amide mixtures can be separated from one another by fractional crystallization.

The 5 (6) -hydroxymethylsulfonylbenzimidazoles can be prepared in various ways. The ethyl esters of 1-sulfonyl-2-substituted-5 (6) -benzimidazole carboxylic acids can be reduced chemically to form the corresponding hydroxymethyl compounds. Reduction of ethyl 1-dimethylaminosulfonyl-2-acetamido-5 (6) -benzimidazole carboxylate with sodium bis (2-methoxyethoxy) aluminum hydride in tetrahydrofuran gives, for example, 1-dimethylaminosulfonyl-2-acetamido-5 (6) -hydroxymethylbenzimidazole. A better method is to react a sulfonyl chloride, the formula R1SO2CI, with the corresponding 2-substituted 5 (6) -hydroxymethylbenzimidazole. The 5 (6) -hydroxymethylbenz-imidazole required as starting material for this can be prepared from the corresponding ethyl-2-substituted-5 (6) -benzimidazole carboxylic acid by reduction with sodium bis (2-methoxyethoxy) aluminum hydride in an aprotic solvent as described above will. The preferred process for producing large amounts of the hydroxymethylsulfonylbenzimidazoles required as intermediates is based on 4-chloro-3-nitrobenzyl alcohol. The benzyl alcohol is ammoniated to 4-amino-3-nitrobenzyl alcohol. The nitro alcohol is catalytically hydrogenated with 4-hydroxymethyl-o-phenylenediamine. The phenylenediamine obtained in this way is converted into the desired intermediate product, namely the 2-substituted 5 (6) -hydroxymethylbenzimidazole, by ring closure methods known in benzimidazole chemistry.

The sulfonylbenzimidazole carboxylic acids and their hydrazides are normally only suitable as intermediates which are converted into the corresponding esters or carboxamides

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can. However, the l-dimethylaminosulfonyl-2-amino-6-benzimida-zolcarboxylic acid inhibits the Polio-I-Viras in a concentration of 100 mg / ml (see Table I).

The corresponding substituted o-phenylenediamines are also required to prepare the benzimidazoles required as starting products. To this end, 3-nitro-4-chloro-benzotrifluoride can be ammoniated and then reduced to 3,4-diaminobenzotri-fluoride. 2- (3,4-diaminophenyl) acetic acid can be prepared, for example, by acetylating 2- (4-aminophenyl) acetonitrile with acetic anhydride in pyridine. The 2- (4-acetamidophenyl) acetonitrile obtained is nitrated, for example, in acetic anhydride to give 2- (3-nitro-4-acetamidophen-yl) acetonitrile. The Nitrii obtained is hydrolyzed with concentrated hydrochloric acid, whereby 2- (3-nitro-4-aminophenyl) acetic acid is obtained after neutralization. The nitro acid is hydrogenated at room temperature and a pressure of 4.22 kg / cm 2 with palladium-on-carbon to give 2- (3,4-diaminophenyl) acetic acid.

The acid can be esterified with Ci-Cs-carbinols in the presence of acid catalysts. Similarly, the preparation of 2- (3,4-diaminophenyl) propionic acid starts from 2- (4-aminophenyl) propionitrile, the procedure being the same as above for the preparation of diaminophenylacetic acid.

4-Cyano-o-phenylenediamine can be prepared from 4-aminobenzonitrile by acetylating this compound (a) to 4-acetamidobenzonitrile, (b) nitrating it to 3-nitro-4-aceta-midobenzonitrile, (c) from the nitro compound with PCls in pyridine to form 3-nitro-4-aminobenzonitrile, the acetyl group is split off and (d) the nitro group of the compound obtained is hydrogenated at a pressure of 4.22 kg / cm 2 with Raney nickel, whereby 3,4-diaminobenzoni -tril (4-cyano-o-phenylenediamine).

4-Methylsulfonyl-o-phenyldiamine can be prepared by nitriding (4-chlorophenyl) methylsulfone, which initially gives (3-nitro-4-chlorophenyl) methylsulfonate. The chlorine group of this compound is then ammoniated to form (3-nitro-4-aminophenyl) methylsulfone. The nitrosulfone obtained in this way is finally hydrogenated with ruthenium-on-carbon, whereby the 4-methyl-sulfonyl-o-phenylenediamine is obtained.

The benzimidazoles, which are required as starting materials for the above process, can be prepared by various processes. The 2- (H) and 2-methylbenzimidazoles required for this can be obtained by cyclizing the corresponding o-phenylenediamines with formic acid or acetic acid according to the method described by Phillips in J. Chem. Soc. 2398 (1928). The 2-aminobenzimidazoles are prepared, for. B. by cyclizing o-phenylenediamines with cyanogen bromide according to that of Buttle et al. in organic. Chem. J. 32,1101 (1938) described methods or according to GB-PS 551 524. Ethyl-2-amiho-5-benz-imidazole-carboxylates are described by Paget et al. in J. Med. Chem. 12, 1010 (1969). The 2-methylaminobenzimidazoles required as starting products can be prepared by cyclodesulfurization of the corresponding 1- (2-aminophenyl) -3-methyl-2-thioureas with mercury oxide in accordance with US Pat. No. 3,455,948. The 2-acetamidobenzimi-dazoles are prepared, for. B. by acylating the corresponding 2-aminobenzimidazoles. Examples of such benzimidazoles which can be reacted with the suitable sulfonyl chlorides are the 2- (H) -, 2-amino, 2-methyl, 2-methylamino and 2-acetamidobenzimidazoles which are in position 5 (6) by Ci -Cs-alkoxycarbonyl, Ci-Cs-alkoxycarbonylmethyl, l- (Ci-Cs-alkoxycarbonyl) ethyl, cyano, methylsulfonyl or trifluoromethyl are substituted.

Of the sulfonyl chlorides required as starting products are methanesulfonyl chloride (mesyl chloride), isopropylsulfonyl chloride, dimethylsulfamoyl chloride, benzenesulfonyl chloride,

2-thiophene sulfonyl chloride and 2-acetamido-4-methyl-5-thiazole sulfonyl chloride are commercially available. The production of 3-thiophene sulfonyl chloride and 2- (or 3) furansulfonyl chloride is described by Arcoria et al. described [see J. Org. Chem. 39, 1689 and 3595 (1974)]. 2-thiazole sulfonyl chloride, 2-thiadiazole sulfonylchloride, 2-methyl-5-thiadiazole sulfonyl chloride and 2-methylamino-5-thiadiazole sulfonyl chloride can be obtained from 2-thiazole thiol, 2-thiadiazole thiol, 2-methyl-5-thiadiazole thiol and thioladiol. Obtain 5-thiadiazole thiol by oxidizing the thiol function with bromine or chlorine in aqueous solution. Ci — Cs alkyl and C3 — C7 cycloalkylsulfonyl chlorides can be prepared by chlorinating the appropriate alkyl thiol or by reacting sulfuryl chloride with sodium alkylsulfonates derived from the corresponding carbinols and sulfuric acid. The N, N-dialkylsulfamoyl chlorides can be prepared according to the method described by Bindely et al. in J. Am. Chem. Soc. 61, 3250 (1939) described processes by reacting a secondary amine salt with sulfuryl chloride. These compounds can optionally also be reacted by reacting a chloramine of the formula

R4R5N-CI

Manufacture with sulfur dioxide at temperatures from -5 to 30 ° C. The chloramines are e.g. B. prepared by reacting the corresponding secondary amines with antimony pentachloride, sodium hypochlorite or sulfuryl chloride.

Further examples of sulfonyl chlorides which can be reacted with the benzimidazoles are ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, amyl-1, isoamyl, sec-isoamyl and tert-amylsulfonyl chloride.

Sulfamoyl chlorides which can be used are, for example, diethyl, dipropyl, N-methyl-N-ethyl, N-methyl-N-propyl, N-ethyl-N-propyl, N-methyl-N-isopropyl, N- Ethyl-N-isopropyl, N-propyl-N-isopropyl, diisopropyl, pyrrolidino, piperidino and morpholinosulfamoyl chloride.

For reasons of the same nomenclature, the sulfonylbenzimidazoles are referred to as sulfonyl derivatives. For example, the reaction product obtained by reacting dimethylsulfamoyl chloride with ethyl 2-amino-5-benzimidazolecarboxylate is referred to as ethyl-l-dimethylamino-nosulfonyl-2-amino-5 (6) -benzimidazole carboxylate, and not as ethyl-l- dimethylsulfamoyl-2-amino-5 (6) -benzimidazole carboxylate.

The effectiveness of the compounds of the formula I according to the invention is determined by the following tests:

Examination procedure

Kidney cells (BSC-1) or hela cells (5-3) of the African green monkey are left in 25 cc Falcon flasks at a temperature of 37 ° C in medium 199 with 5% inactivated fetal bovine serum (FBS), penicillin (150 units per ml) and streptomycin (150 Hg / ml) grow. As soon as confluent monolayers have formed, the supernatant growth medium is removed and 0.3 ml of a corresponding virus dilution (echo, Mengo, Coxsackie, polio or rhinovirus) is added to each flask. After adsorption for 1 hour at room temperature, the virus-infected cell area is covered with a medium which contains a part of 1% Ionagar No. 2 and a part of double-strong medium 199 with FBS, penicillin and streptomycin, and furthermore active compound concentrations of 100. 50, 25, 12, 6, 3 and 0 micrograms per milliliter (µg / ml). The flask, which contains no active ingredient, serves as a control for the experiment. The stock solutions of the sulfonylbenzimidazole compounds are each prepared in dimethyl sulfoxide in concentrations of 104 [ig / ml. The polio, coxsackie,

6

5

10th

is

20th

25th

30th

35

40

45

so

55

60

65

7 617428

Flasks containing echo and mengoviruses are inhibited, 72 use as a measure of effectiveness. The 50-pro

Incubated for hours at 37 ° C, and the flask with rhinovirus inhibition is expressed by the value Iso, incubated for 120 hours at 32 ° C. On the areas where the virus has led to infection and where the results from the above experiment are shown in

When cells have reproduced, leaflets can be seen. Each flask expressed inhibition values for type I poliovirus, as this is easily grown with a solution of 10% formalin and 2% sodium virus, and acetate is added to match the results in order to inactivate the virus and lead to cell buildup. To fix the effectiveness of the preferred ones according to the invention on the surface. The virus platelets become compounds, however, are also used against other virus cultures.

regardless of their size confirmed after staining the surrounding doors. For example, ethyl-l-dimethylami-

Cell areas counted with crystal violet. The platelet count io nosulfonyl-2-amino-6-benzimidazole carboxylate in concentrated

At each active ingredient concentration, the lungs are compared with the controls of 3.0 [xg / ml coxsackie (A9, A21, B5), echovirus count. The effectiveness of each investigated (strains 1-4), Mengorhinovirus (25 strains) and polio (type ten compound is shown as a percentage platelet reduction or I ,. II, III). The experiment with various sulfonyl

percentage inhibition indicated. Alternatively one can get the results obtained from benzimidazoles from the following

Active ingredient concentration, which shows the platelet formation by 50%, is shown in Table I.

Table I

percentage reduction in leaflets (polio I)

Drug concentration (ng / ml)

R1

R2

R3

100

50

25th

12

6

3rd

1.5

0.75

(chs) 2N

H

6-C02C2H5

64

0

0

0

0

(ch3> n ch3

6-C02C2H5

90

80

50

22

0

(ch3) 2n nh2

5-C02C2H5

100

98

72

37

25th

0

(ch3) 2N

nh2

6-C02C2H5

100

100

100

100

100

96

52

methyl

NH2

6-c02c2h5

87

51

24th

0

0

Isopropyl

NH2

6-c02c2h5

100

100

98

54

24th

(ch3) 2n

NH2

5-CF3

62

64

64

61

51

0

Pyrrolidino nh2

5 (6) -c02c2h5 +

100

100

100

99

63

Piperidino nh2

5 (6) -c02c2h5 +

toxic toxic

100

100

3rd

Morpholino nh2

5 (6) -c02c2h5 +

100

99

86

3rd

0

(ch3) 2N

nh2

6-c02ch3

100

97

60

35

(CHs) 2N

nh2

6-CO2C4H9

100

98

63

28

ch3 (c2h5) n nh2

6-CO2C2H5

100

100

100

83

51

ch3 (c3h7) n nh2

6-CO2C2H5

100

100

90

52

35

(C2Hs) 2N

nh2

6-CO2C2H5

100

100

87

43

25th

(ch3> n nh2

6-cooh

50

34

23

17th

(ch3) 2n nh2

5-CONH2

55

32

30th

25th

23

8th

(ch3) 2n nh2

6-CONH2

100

100

100

78

43

36

27th

(ch3) 2n nh2

5-CONHC2H5

97

54

21st

7

(ch3) 2n nh2

6-CONHC2H5

100

100

100

99

80

40

9

+ Mixtures of isomers

Table / (continued)

Percentage Reduction of Papers (Polio I)

Drug concentration (ng / ml)

Example No.

R1

R2

R3

100

50

25th

12

6

3rd

1.5

0.75

13

2-thienyl

NH2

5 (6) -C02Et light light

100

100

100

73

16

18th

toxic toxic

14

2-acetamido-4-

methylthiazole

5-yl

NH2

5 (6) -C02Et

100

100

99

89

56

47

26

15

2-methylamino

1,3,4-thiadia-

zol-5-yl

NH2

5 (6) -C02Et

100

100

75

20th

0

0

0

0

51

Me2N

NH2

5 (6) -C02-t-But *

toxic toxic

57

100

100

100

100

100

52

Cyclohexyl

NH2

5 (6) -C02Et *

weak weak weak

100

100

91

44

13

toxic toxic toxic

53

Cyclopentyl

NH2

6-C02Et

100

100

100

100

100

97

40

24th

53

Cyclopentyl

NH2

5-C02Et

100

100

99

60

29

12

0

0

54

Cycloheptyl

NH2

5 (6) -C02Et *

weak weak weak

100

97

43

19th

0

toxic toxic toxic

55

Pyrrolidino

NH2

5 (6) -C02Et *

100

100

100

100

100

70

37

14

56

Piperidino

NH2

5-C02Et toxic toxic

100

100

100

31

0

57

Morpholino

NH2

5 (6) -C02Et *

100

100

98

85

2nd

0

0

'58

Me2N

NHMe

6-CQ2Et

100

92

70

37

14

0

0

617428

Table I (continued) Percentage Reduction of Papers (Polio I)

example

Drug concentration (ng / ml)

No.

R1

R2

R3

100

50

25th

12

6

3rd

1.5

0.75

59

Me2N

NH2

5 (6) -CH2C02-Et: 5

100

77

57

44 '

3rd

0

0

60

Me2N

NH2

5 (6) -CH- (CH3) C02CH3: |

= 100

100

76

35

17th

6

0

0

61

Me2N

NH2

6-CO2N2H3

77

39

25th

0

0

0

0

63

Me2N

NH2

5 (6) -CN *

100

100

64

15

0

0

0

0

65

Me2N

NH2

5-CF3

71

63

63

61

50

0

0

0

62

Me2N

NH2

5 (6) -CONHOCH3: |!

100

100

100

100

100

92

53

27th

* Mixtures of isomers Me = Methyl Et = ethyl

The active ingredient concentrations of various esters, which are not ethyl esters, and which inhibit the formation of viral leaflets by 50% (Iso), are summarized in the following Tables II and III.

Table II

Virus inhibition (I50) by esters of 1-dimethylaminosulfonyl-2-amino-5 (6) -benzimidazole carboxylic acids

Iso (t »g / ml)

Ester2

Polio I

Rhino 3

Coxsackie A21

(6) methyl

3rd

0.75

3rd

Propyl

1.5

3rd

1.5

(6) -isopropyl

0.35

0.75

1.5

Allyl

3-6

Propargyl

3-6

Butyl

3rd

0.75

3rd

(5) -isobutyl

3rd

3-6

3rd

(6) -Neopentyl

0.75

0.75

1.5

(5) -Neopentyl

3rd

Octyl

50

(6) -cyclohexyl

0.35

1.5

0.75

Cyclohexylmethyl

3-6

1.5

Benzyl

6

alpha-methylbenzyl

3rd

5 (6) -N-methoxy-

carboxamido

1.5

<12

6

30th

40

* If the active ingredient used is an isomer, this is indicated by the number in parentheses before the ester residue, if nothing is specified, then the active ingredient used is an isomeric mixture. The [xg / ml] is the active substance concentration in (xg / ml.

Table III

Virus inhibition (Iso) by esters of 1-dimethylaminosulfonyl-2-acetamido-5 (6) -benzimidazole carboxylic acids

I50 ((ig / ml)

Ester'3

Polio I

Rhino 3 Coxsackie A21

Isopropyl 0.75

(5) -isobutyl 3

(6) -Isobutyl 0.75 neopentyl 1.5-3 sec-butyl 0.75

(5) -cyclopropylmethyl 6

(6) -cyclopropylmethyl 0.75-1.5 cyclohexylmethyl 3 3-methylcyclohexylmethyl 3 l- (cyclopropyl) ethyl 0.75 cyclobutyl 0.35 cyclohexyl 1.5 (6) -phenyl 3-6

<3 0.75-1.5

1.5 1.5-3

ss

60

<5 <5

1.5 1.5

* If the active ingredient used is an isomer, this is the number in in front of the ester residue

If nothing is given in parentheses, the active ingredient used is an isomeric mixture. The term | Ag / ml means the active substance concentration in | .ig / ml.

20th

Table III (continued)

Example No.

I50 (ng / ml)

Polio I

Rhino 3

Cox A21

52

1.5

0.75

1.5

55

1.5

3rd

6

65

6

12

-

The sulfonylbenzimidazoles obtained according to the invention were investigated as pure compounds and as isomer mixtures. Both isomers inhibit viral growth, with the 6 isomer generally being more effective than the 5 isomer. For example, ethyl I-dimethylaminosulfonyl-2-amino-6-benzimidazole carboxylate completely inhibits polio I virus at a concentration of only 3.0 pg / ml. With a 5-isomer there is complete inhibition at a concentration of 12.0 (ig / ml.

The preferred compounds of formula I include the 1- (Ci-Cs) -alkylsulfonyl-2-amino-5 (6) -benzimidazole carboxylate esters. The 1- (aminosulfonyl) -2-amino-5 (6) -benzimidazole carboxylate esters are particularly preferred. The most preferred compounds are the ethyl, propyl, isopropyl, neopentyl, cyclobutyl, cyclohexyl and 1- (cyclopropyl) ethyl esters of l- (N, N, -dialkylaminosulfonyl) -2-amino-5 (6 ) -benzimidazole carboxylic acids. The 6 isomers are preferred over the 5 isomers.

Compounds which fall under the formula I given above suppress the growth of various viruses after addition to a medium in which the virus grows. The compounds prepared according to the invention can therefore be used in aqueous solution, preferably together with a surface-active agent, for the decontamination of surfaces on which polio, coxsackie or rhinoviruses or other viruses are present, and such surfaces are, for example, glassware used in hospitals and the working areas in hospitals and similar areas in the production of food.

The active compounds according to the invention can also be administered to warm-blooded animals and humans in doses of 1 to 300 mg per kg of body weight. The administration can be repeated periodically as required. The antiviral compound is generally administered every 4 to 6 hours.

The compounds obtained according to the invention are preferably used in combination with one or more adjuvants which are suitable for the particular mode of administration. In this way, the new active ingredients are modified in the case of oral administration, for example using pharmaceutical diluents and carriers, such as lactose, sucrose,

Starch powder, cellulose, talc, magnesium stearate, magnesium oxide, calcium sulfate, acacia powder, gelatin, sodium alginate, sodium benzoate or stearic acid. Preparations of this type can be formulated into tablets for convenient administration or enclosed in capsules. In addition, the active ingredients can also be administered parenterally.

The compounds produced according to the invention can also be mixed with a liquid and administered as a nasal drop or intranasal spray.

Typical sulfonylbenzimidazoles obtained according to the invention are the following compounds:

1-methylsulfonyl-2-amino-5 (6) -cyanobenzimidazole,

l-ethylsulfonyl-2-methyl-5 (6) -methylsulfonyl-

benzimidazole,

l-propylsulfonyl-2-amino-5 (6) -trifluoromethyl-benzimidazole,

l-isopropylsulfonyl-2-methylamino-5 (6) -methylsulfonylbenzimidazole,

l-butylsulfonyl-5 (6) -trifluoromethyl-benzimidazole,

1-isobutylsulfonyl-2-methyl-5 (6) -hydroxymethyl-benzimidazole,

1- (sec-butylsulfonyl) -2-amino-5 (6) -benzimidazole-carboxamide,

l- (tert-butylsulfonyl) -2-methylamino-5 (6) -

benzimidazole carboxylic acid hydrazide,

Neopentyl-l-cyclopentylsulfonyl-2-acetamido-5 (6) -

benzimidazole carboxylate,

l-morpholinosulfonyl-2-amino-5 (6) -N-propyl-

benzimidazole carboxamide,

Propargyl-1-piperidinosulfonyl-2-methylamino-5 (6) -benzimidazole carboxylate,

1- (2-methylamino-l, 3,4-thiadiazol-5-yl) sulfonyl-2-

amino-5 (6) -N-methoxybenzimidazole carboxamide,

l-dipropylamine sulfonyl-2-acetamido-5 (6) -N-ethyl-

benzimidazole carboxamide,

1 - (2-methyl-l, 3,4-thiadiazol-5-yl) sulfonyl-5 (6) -

benzimidazole carboxylic acid alpha-methylbenzyl ester,

1- (N-methyl-N-propylaminosulfonyl) -2-amino-5 (6) -

N-isopropoxybenzimidazole carboxamide,

1- (2-thiophene) sulfonyl-2-acetamido-5 (6) -hydroxy-

methylbenzimidazole,

1- (2-acetamido-4-methylthiazol-5-yl) sulfonyl-2-methyl-5 (6) -hydroxymethylbenzimidazole, l-piperidinosulfonyl-2-acetamido-5 (6) -hydroxy-methylbenzimidazole,

1- (N-methyl-N-propylaminosulfonyl) -2-amino-5 (6) -

hydroxymethylbenzimidazole,

Neopentyl-l-isopropylsulfonyl-2-methylamino-5 (6) -

benzimidazole carboxylate,

Propargyl-1-cyclohexylsulfonyl-2-methyl-5 (6) -

benzimidazole carboxylate,

phenyl l- (N-methyl-N-ethylaminosulfonyl) -2-amino-5 (6) -benzimidazole, phenyl l-cyclopropylsulfonyl-5 (6) -benzimidazole,

l-piperidinosulf.onyl-2-acetamido-5 (6) -benzimidazole-

phenyl carboxylate,

l-amylsulfonyl-5 (6) -benzimidazole carboxylic acid,

l-isoamylsulfonyl-2-methyl-5 (6) -cyanobenzimidazole,

1- (sec-isoamylsulfonyl) -2-amino-5 (6) -methylsulfonyl-

benzimidazole,

1 - (tert-amylsulfonyl) -2-methylamino-5 (6) -trifluoromethylbenzimidazole,

1- (N-methyl-N-ethylaminosulfonyl) -2-methyl-5 (6) -methylsulfonylbenzimidazole,

617 428

1- (N-methyl-N-propylaminosulfonyl) -2-amino-5 (6) -

trifluoromethylbenzimidazole,

l- (N-methyl-N-isopropylaminosulfonyl) -2-methyl-

amino-5 (6) -hydroxymethylbenzimidazole,

l-diethylaminosulfonyl-5 (6) -methylsulfonyl-

benzimidazole,

1- (N-ethyl-N-propylaminosulfonyl) -2-methyl-5 (6) -trifluoromethylbenzimidazole,

1- (N-ethyl-N-isopropylaminosulfonyl) -2-amino-5 (6) -

benzimidazole carboxamide,

l-dipropylaminosulfonyl-2-methylamino-5 (6) -

benzimidazole carboxylic acid hydrazide,

1- (N-propyl-N-isopropylaminosulfonyl) -5 (6) -

benzimidazole carboxylic acid,

1 -diisopropylaminosulfonyl-2-methyl-5 (6) -

cyanobenzimidazole,

l-benzenesulfonyl-2-amino-5 (6) -methylsulfonyl-benzimidazole,

l-pyrrolidinosulfonyl-2-methylamino-5 (6) -trifluoromethylbenzimidazole,

phenyl l-benzenesulfonyl-2-amino-5 (6) -benzimidazole,

Cyclobutyl-l- (2-thiazole) sulfonyl-2-acetamido-5 (6) -benzimidazole carboxylate,

1- (2-acetamido-4-methylthiazol-5-yl) sulfonyl-2-methyl

amino-5 (6) -hydroxymethylbenzimidazole,

1- (2-methylamino-l, 3,4-thiadiazol-5-yl) sulfonyl-2-

methyl-5 (6) -N-butylbenzimidazole carboxamide,

1-cyclopropylsulfonyl-2-amino-5 (6) -hydroxymethyl-

benzimidazole,

phenyl 1- (3-furan) sulfonyl-2-acetamido-5 (6) -benzimidazole,

l- (2-Acetamido-4-methylthiazol-5-yl) sulfonyl-2-methyl-5 (6) -benzimidazolecarboxylic acid-l- (cyclopropyl) ethyl ester, l- (2-thiophene) suIfonyl-2-acetamido-5 ( 6) -N-butoxy-benzimidazole carboxamide,

1-diethylaminosulfonyl-2-methyl-5 (6) -N-butyl-benzimidazole carboxamide,

Neopentyl-1-cyclohexylsulfonyl-2-acetamido-5 (6) -benzimidazole carboxylate,

Allyl-l- (2-methylamino-l, 3,4-thiadiazol-5-yl) sulfonyl-

2-methiamino-5 (6) -benzimidazole carboxylate, propargyl-1- (1,3,4-thiadiazol-2-yl) sulfonyl-2-acetamido-5 (6) -benzimidazole carboxylate,

l- (l, 3,4-thiadiazol-2-yl) sulfonyl-2-methylamino-5 (6) -N-propylbenzimidazolecarboxamide, l-isopropylsulfonyl-2-methyl-5 (6) -benzimidazolecarboxylic acid cyclobutylmethyl ester,

l-Dimethylaminosulfonyl-2-acetamido-5 (6) -benzimidazole-carboxylic acid-l- (cyclohexyl) ethyl ester, l- (2-methylamino-1,3,4-thiadiazol-5-yl) sulfonyl-2-methyl-5 (6) -benzimidazolecarboxylic acid-alpha-methyl-benzyl ester,

1-Cycloheptylsulfonyl-2-amino-5 (6) -benzimidazole-carbonic acid 1 - (cycloheptyl) ethyl ester, l-piperidinosulfonyl-5 (6) -hydroxymethylbenzimidazole, l-morpholinosulfonyl-2-methyl-5 (6) -methylsulfonyl benzimidazole,

l-methylsulfonyl-5 (6) -benzimidazole carboxylic acid 2,2,4-trimethyl-1-pentyl ester,

l-ethylsulfonyl-2-methyl-5 (6) -benzimidazolecarboxylic acid isooctyl ester,

2-ethylhexyl l-propylsulfonyl-2-amino-5 (6) -benzimidazole carbonate,

l-isopropylsulfonyl-2-methylamino-5 (6) -benzimidazole-carboxylic acid 2-octyl ester, l-butylsulfonyl-5 (6) -benzimidazolecarboxylic acid-2-heptyl ester,

9

s

10th

15

20th

25th

30th

35

40

45

so

55

60

65

617428

l-isobutylsulfonyl-2-methyl-5 (6) -benzimidazole carbonate, octyl ester,

1- (sec-butylsulfonyl) -2-amino-5 (6) -benzimidazole carbonate,

l- (tert-butylsulfonyl) -2-methylamino-5 (6) -

benzimidazole carboxylic acid heptyl ester,

1-amylsulfonyl-5 (6) -benzimidazolecarboxylic acid octyl ester,

l-isoamylsulfonyl-2-methyl-5 (6) -benzimidazolecarbon-

acid 4-methyl-2-pentyl ester,

1 - (1,2-dimethylpropylsulfonyl) -2-amino-5 (6) -

benzimidazole carboxylic acid isooctyl ester,

1- (tert-amylsulfonyl) -2-methylamino-5 (6) -

benzimidazole carboxylic acid propyl ester,

Propargyl-1-pyrrolidinosulfonyl-2-acetamido-5 (6) -

benzimidazole carboxylate,

Cyclobutyl-l- (N-methyl-N-isopropylaminosulfonyl) -2-

acetamido-5 (6) -benzimidazole carboxylate,

1- (2-acetamido-4-methylthiazol-5-yl) sulfonyl-2-

amino-5 (6) -N-isopropylbenzimidazole carboxamide,

1- (2-thiophene) sulfonyl-2-methyl-5 (6) -N-isopropoxy-

benzimidazole carboxamide,

Neopentyl-l- (2-thiazole) sulfonyl-2-methyl-5 (6) -

benzimidazole carboxylate,

Allyl-l-piperidinosulfonyl-2-methyl-5 (6) -

benzimidazole carboxylate,

Neopentyl-l- (2-methylamino-l, 3,4-thiadiazol-5-yl) -

sulfonyl-2-methyl-5 (6) -benzimidazole carboxylate,

l- (N-methyl-N-propylaminosulfonyl) -5 (6) -benzimidazole-

carboxylate-l- (cyclobutyl) ethyl ester,

l-dimethylaminosulfonyl-2-acetamido-5 (6) -

benzimidazole carboxylic acid phenyl ester,

1- (2-acetamido-4-methylthiazol-5-yl) sulfonyl-2-

amino-5 (6) -benzimidazole carboxylic acid phenyl ester,

l-isopropylsulfonyl-2-amino-5 (6) -benzimidazolecarbon-

acid phenyl ester,

l-cyclopropylsulfonyl-2-methyl-5 (6) -benzimidazole-

carboxylic acid l- (cyclopropyl) ethyl ester,

Propargyl-1-dipropylaminosulf onyl-2-methylamino-

5 (6) -benzimidazole carboxylate,

1 - (2-furan) sulfonyl-2-acetamido-5 (6) -benzimidazole-

carboxylic acid cyclopropyl methyl ester,

1-benzenesulfonyl-2-amino-5 (6) -benzimidazolecarbon-

acid cyclopropyl methyl ester,

Cyclobutyl-l- (N-methyl-N-ethylaminosulfonyl) -2-

methyl 5 (6) benzimidazole carboxylate,

1-dimethylaminosulfonyl-2-amino-5 (6) -benzimidazole-

phenyl carboxylate,

l-dimethylaminosulfonyl-5 (6) -benzimidazolecarbon-

2,2,4-trimethyl-1-pentyl acid,

1 - (N-methyl-N-ethylaminosulfonyl) -2-methyl-5 (6) -

isopropyl benzimidazole carboxylate,

1 - (N-methyl-N-propylaminosulfonyl) -2-amino-5 (6) -

benzimidazole carboxylic acid butyl ester,

1- (N-methyl-N-isopropylaminosulfonyl) -2-methylamino

5 (6) -benzimidazole carboxylic acid isobutyl ester,

l-diethylaminosulfonyl-5 (6) -benzimidazolecarboxylic acid-

hexyl ester,

methyl l-(N-ethyl-N-propylaminosulfonyl) -2-methyl-5 (6) -benzimidazole carboxylate, 2-heptyl l- (N-ethyl-N-isopropylaminosulfonyl) -2-amino-5 (6) benzimidazole carboxylic acid benzoyl acid, 1-dipropylaminosulfonyl-2-methylamino-5 (6) -benzimidazolecarboxylic acid isobutyl ester, 1- (N-propyl-N-isopropylaminosulfonyl) -5 (6) -benzimidazolecarboxylic acid propyl ester,

1-diisopropylaminosulfonyl-2-methyl-5 (6) -benzimidazolecarboxylic acid 2-ethylhexyl ester,

10th

l-benzenesulfonyl-2-methylamino-5 (6) -benzimidazole-carboxylic acid butyl ester, l-pyrrolidinosulfonyl-2-methylamino-5 (6) -benzimidazolecarboxylic acid-2-octyl ester, s l-piperidinosulfonyl-5 (6) -benzimidazylcarbonate, acidhehe

l-morpholinosulfonyl-2-methyl-5 (6) -benzimidazole-carboxylic acid 2-ethyl-l-butyl ester,

Neopentyl-1 - (1,3,5 -thiadiazol-2-yl) sulfonyl-2-10 methylamino-5 (6) -benzimidazole carboxylate, l-benzenesulfonyl-2-methyl-5 (6) -benzimidazole-carboxylic acid cycloheptylmethyl ester, neopentyl- l-morpholinosulfonyl-2-acetamido-5 (6) -benzimidazole carboxylate, ls cyclohexyl-l-cyclohexylsulfonyl-2-amino-5 (6) -benzimidazole carboxylate, benzyl-l- (l, 3,4-thiadiazol-2-yl) sulfonyl-2-methyl-5 (6) -benzimidazole carboxylate,

Allyl-1 - (2-methyl-1,3,4-thiadiazol-5-yl) sulfonyl-5 (6) -20 benzimidazole carboxylate,

Allyl-l-isopropylsulfonyl-2-amino-5 (6) -benzimidazole-carboxylate,

Propargyl-l-benzenesulfonyl-2-acetamido-5 (6) -benzimidazole carboxylate, 25 cyclobutyl-l- (2-acetamido-4-methylthiazol-5-yl) sul-fonyl-2-methylamino-5 (6) -benzimidazole carboxylate, Neopentyl-l- (2-methyl-l, 3,4-thiadiazol-5-yl) sul-fonyl-2-methyl-5 (6) -benzimidazole carboxylate,

1-pyrrolidinosulfonyl-2-acetamido-5 (6) -benzimidazole-30 carboxylic acid-l- (cyclopropyl) ethyl ester,

Benzyl-l- (2-thiophene) sulfonyl-2-acetamido-5 (6) -benzimidazole carboxylate,

Propargyl-1 - (2-methyl-1,3,4-thiadiazol-5-yl) sulfonyl-

2-amino-5 (6) -benzimidazole carboxylate,

35 isopropyl-1- (3-furan) sulfonyl-2-methylamino-5 (6) -benzimidazole carboxylate,

1-cyclobutylsulfonyl-5 (6) -benzimidazolecarboxylic acid 1- (cyclopropyl) ethyl ester,

Cyclobutyl-1- (N-methyl-N-ethylaminosulfonyl) -2-40 amino-5 (6) -benzimidazole carboxylate,

2- (l-methylsulfonyl-2H-benzimidazol-5-yl) acetic acid

4-methyl-2-pentyl ester,

2- (l-benzenesulfonyl-2-methylbenzimidazol-5-yl) 2-methyl-1-pentyl acetate, 45 2- (l-dimethylaminosulfonyl-2-acetamidobenzimidazol-5-yl) -acetic acid ethyl ester,

Tert-butyl 2- (l-morpholinosulfonyl-2-aminobenzimidazol-5-yl) -acetate,

Methyl 2- (l-methylsulfonyl-2H-benzimidazol-5-yl) propion-50,

2- (l-benzenesulfonyl-2-aminobenzimidazol-5-yl) propionic acid isopropyl ester,

2- (l-Dimethylaminosulfonyl-2-acetamidobenzimidazol-5 -yl) -proponic acid sec. -butyl ester, 55 2- (l -pyrrolidinosulfonyl-2-methylaminobenzimidazole-

5-yl) -propionic acid isooctyl ester, 2- (l-diisopropylaminosulfonyl-2-methylbenzimidazol-5-yl) -propionic acid-2-ethylhexyl ester,

1-methylsulfonyl-5 (6) -cyanobenzimidazole, 60 1-benzenesulfonyl-5 (6) -cyanobenzimidazole, l-isopropylsulfonyl-2-acetamido-5 (6) -cyanobenzimidazole,

l-dimethylaminosulphonyl-2-amino-5 (6) -cyanobenzimidazole, 65 l-pyrrolidinosulfonyl-2-amino-5 (6) -hydroxymethylbenzimidazole, l- (N-ethyl-N-propylaminosulfonyl) -2-acetamido-5 (6 ) -cyanobenzimidazole,

11

617428

Neopentyl-1- (N-methyl-N-propylaminosulfonyl) -2-acetamido-5 (6) -benzimidazole carboxylate, 1 - (2-methyl-1,3,4-thiadiazol-5-yl) sulfonyl-5 (6) -benzimidazole carboxylic acid-alpha-methylbenzyl ester, propargyl-1- (N-methyl-N-isopropylaminosulfonyl) -2-acetamido-5 (6) -benzimidazole carboxylate,

1-cyclopropylsulfonyl-2-methyl-5 (6) -benzimidazole-carboxylic acid hydrazide,

1 - (2-thiophene) sulfonyl-2-methylamino-5 (6) -benzimidazole carboxamide,

1- (N-ethyl-N-propylaminosulfonyl) -2-acetamido-5 (6) -benzimidazole carboxamide,

l-piperidinosulfonyl-2-amino-5 (6) -benzimidazole-carbonic acid hydrazide,

l-benzenesulfony] -2-acetamido-5 (6) -N-ethoxy-benzimidazole carboxamide,

l-dimethylaminosulfonyl-2-amino-5 (6) -N-isopropoxy-benzimidazole carboxamide,

1 - (2-methyl-1,3,4-thiadiazol-5-yl) sulf onyl-2-methyl-

amino- 5 (6) -benzimidazole carboxylic acid hydrazide,

1- (2-acetamido-4-methylthiazol-5-yl) -2-amino-5 (6) -

benzimidazole carboxamide,

l- (l, 3,4-thiadiazol-2-yl) sulfonyl-2-methyl-5 (6) -

benzimidazole carboxylic acid hydrazide,

l-dipropylaminosulfonyl-2-methyl-5 (6) -benzimidazole-

carboxylate phenyl ester,

l-dimethylaminosulfonyl-5 (6) -benzimidazole-carbonic acid hydrazide,

1- (2-acetamido-4-methylthiazol-5-yl) sulfonyl-2-

acetamido-5 (6) -benzimidazolecarboxylic acid hydrazide,

l- (l, 3,4-thiadiazol-2-yl) sulfonyl-2-methylamino-5 (6) -

benzimidazole carboxylic acid l- (cyclopropyl) ethyl ester,

Allyl-1-butylsulfonyl-2-amino-5 (6) -benzimidazole-

carboxylate,

1-benzenesulfonyl-2-amino-5 (6) -cyanobenzimidazole, 1-benzenesulfonyl-2-methylamino-5 (6) -hydroxymethyl-benzimidazole,

1-benzenesulfonyl-2-acetamido-5 (6) -trifhiormethyl-benzimidazole,

l-benzenesulfonyl-2-methyl-5 (6) -hydroxymethyl-benzimidazole,

l-dimethylaminosulfonyl-2-acetamido-5 (6) -hydroxy-methylbenzimidazole,

l-dimethylaminosulfonyl-2-acetamido-5 (6) -hydroxy-

methylbenzimidazole and

1-Dimethylaminosulfonyl-2-acetamido-5 (6) -trifluoromethylbenzimidazole.

The preparation of compounds of the formula I is illustrated by the following examples.

example 1

Ethyl l-dimethylaminosulfonyl-5-benzimidazole carboxylate (l-dimethylsulfamoyl-benzimidazole-5-carboxylic acid ethyl ester)

4.8 g (25.0 mmol) of ethyl 5-benzimidazole carboxylate are dissolved in 100 ml of tetrahydrofuran with stirring. The solution thus obtained is then carefully mixed in portions with 1.3 g (27.0 mmol) of sodium hydride in the form of a 50 percent dispersion in mineral oil, whereupon 5 ml of dry dimethylformamide are added. 25 mmol (3.6 g) of dimethylsulfamoyl chloride in 10 ml of dry tetrahydrofuran are then added, and the reaction mixture is heated to reflux for 16 hours. Subsequent evaporation of the reaction mixture to dryness in vacuo leaves an oil. The oil is treated with 200 ml of water and poured into an equal volume of water. This solidifies here

Oil after standing and the water is then decanted. The resulting waxy solid is taken up in ethyl acetate, whereupon the solution is decolorized with activated carbon. After filtering off the activated carbon, the filtrate is concentrated to a third of its original volume. When left standing overnight, the product crystallizes out. The crystalline product is washed with a small amount of carbon tetrachloride and collected. This gives 5.0 g of ethyl 1- (dimethylaminosulfonyl) -5-benzimidazole carboxylate.

Analysis for C12H15N3O4S, MG 297:

C H N

Calculated: 48.48 5.09 14.13 Found: 48.42 5.20 14.14

Example 2

Ethyl l-dimethylaminosulfonyl-2-methyl-6-benzimidazole carboxylate 5.1 g (25 mmol) of ethyl 2-methylbenzimidazole-5-carboxylate are stirred in 100 ml of dry tetrahydrofuran (THF). The reaction mixture thus obtained is mixed with 1.3 g of sodium hydride in the form of a 50 percent suspension in mineral oil, and 5 ml of dimethylformamide (T) MF) are then added. 25 ml (3.6 g) of dimethylsulfamoyl chloride in 10 ml of THF are then added and the reaction mixture is heated to reflux with stirring for 6 hours. The reaction mixture is then evaporated to dryness in vacuo. The residue obtained is treated with n-hexane to remove mineral oil, after which the hexane is decanted. The residue is then treated with methanol. The product which precipitates from methanol is collected, giving 300 mg of ethyl 1-dimethylaminosulfonyl-2-methyl-6-benzimidazole carboxylate, which melts at about 124-126 ° C. The structure of the colorless 6-isomer is confirmed by the NMR spectrum in dimethyl sulfoxide.

Analysis for C13H17N3O4S, MG 311:

C.

H

N

Calculated:

50.15

5.50

13.50

Found:

49.97

5.67

13.23

Example 3

Ethyl l-isopropylsulfonyl-2-amino-5 (6) -benzimidazole carboxylate 5 g (25.0 mmol) of ethyl 2-amino-5-benzimidazole carboxylate and 3 ml of triethylamine are stirred with 150 ml of acetone. The reaction mixture is then added dropwise with stirring to 3.6 g (25.0 mmol) of isopropylsulfonyl chloride, which is dissolved in 10 ml of acetone. The reaction mixture is then heated to reflux for 20 hours. The resulting reaction mixture is filtered after cooling, and the filtrate is evaporated to dryness in vacuo. The residue is taken up in a minimal amount of methanol and the whole is then left overnight at room temperature. The crystalline product obtained is filtered off and then washed with a small amount of methanol and ether. A second crop is obtained from the combined washing liquors, so that the total yield is 280 mg of ethyl 1- (isopropylsulfonyl) -2-amino-6-benzimidazole carboxylate, which melts at about 165-167 ° C. and is in the form of colorless crystals. This mate

5

1"

15

20th

25th

30th

35

40

45

50

55

60

65

617428

12

rial is identified as a 6-isomer by nuclear magnetic resonance measurement (NMR) in dimethyl sulfoxide.

The 5-isomer is obtained from the original methanol filtrate, giving 365 mg of ethyl 1-isopropylsulfonyl-2-amino-5-benzimidazole carboxylate, which melts at about 166-168 ° C and is in the form of orange crystals. The structure of this compound is confirmed by NMR spectra in dimethyl sulfoxide.

Analysis for C13H17N3O4S, MG 311:

C.

H

N

Calculated:

50.15

5.50

13.50

Found:

5-isomer:

49.86

5.48

13.24

6-isomer:

49.92

5.26

13.44

Example 4

Ethyl-l- (N-methyl-N-ethylaminosulfonyl) -2-amino-5 (6) -

benzimidazole carboxylate 10 g (50.0 mmol) of ethyl 2-amino-5-benzimidazole carboxylate and 10 ml of triethylamine are stirred in 40 ml of dry acetone. The reaction mixture is then stirred with 8 g (50.0 mmol) of N-methyl-N-ethylsulfamoyl chloride and heated to reflux for 48 hours. After cooling, the reaction mixture obtained is filtered and the filtrate is concentrated in vacuo to half its original volume. The whole is left to stand overnight, whereby the mixture of the isomers crystallizes out of the solution. The product mixture is collected and washed with a small amount of cold methanol.

Analysis for C12H28N4O4S, MG 326:

C.

H

N

Calculated:

47.84

5.56

17.17

Found:

48.09

5.49

16.97

Example 5

Ethyl 1- (N-methyl-N-ethylaminosulfonyl) -2-amino-6-benzimidazole carboxylate (separation of isomers) 4.6 g (14 mmol) of a mixture of isomers of ethyl 1- (N-methyl-N-ethylaminosulfonyl) -2 -amino-5 (6) -benzimi-dazol carboxylate, 1.7 g (30 mmol) of potassium hydroxide and 50 mg of water are refluxed with stirring for 45 minutes. After cooling, the insoluble 6-isomer ethyl ester is filtered off. This gives a yield of 450 mg of ethyl 1- (N-methyl-N-ethylaminosulfonyl) -2-amino-6-benzimidazole carboxylate, which melts at about 170-171 ° C.

Analysis for C13H18N4O4S, MG 326:

C.

H

N

Calculated:

47.84

5.56

17.17

Found:

47.76

5.66

16.95

The basic filtrate is neutralized with in hydrochloric acid. By collecting the solid which precipitates, 2 g of l- (N-methyl-N-ethylaminosulfonyl) -2-amino-5-benzimidazolecarboxylic acid monohydrate of mp 197-199 ° C. are obtained.

Analysis for C11H14N4O4S -H20, MG 316:

C.

H

N

Calculated:

41.77

5.07

17.72

Found:

42.62

4.49

17.89

By further acidifying the neutral filtrate, a small amount of a mixture of the 5- and 6-carboxylic acids is obtained, which is incorporated into a new approach for isomer separation.

Example 6

l-Dimethylaminosulfonyl-2-amino-5 (6) -hydroxy-methylbenzimidazole (A) 2-amino-5 (6) -hydroxymethylbenzimidazole

24.6 g of ethyl 2-amino-5 (6) -benzimidazole carboxylate are suspended in 600 ml of tetrahydrofuran (THF) under nitrogen. The reaction mixture thus obtained is then added dropwise with stirring with 96 ml (0.36 mol) of sodium bis (2-methoxyethoxy) aluminum hydride (RED-AL) in 400 ml of THF in such a way that the temperature does not rise above 35 ° C. The mixture is then heated to reflux for about 20 hours. Then the excess of RED-AL is decomposed by adding 30 ml of water. The mixture is filtered and the filtrate is evaporated to dryness in vacuo. The foamy residue obtained is treated with 150 ml of ethyl acetate and 200 ml of water. The aqueous emulsified phase is separated off. Filtration of the aqueous phase gives a yellow solid. The aqueous filtrate is evaporated in vacuo for a second crop. The combined yield is 12.3 g (65%) of crude 2-amino-5 (6) -hydroxymethylbenzimidazole. An analytical sample of the isomer mixture is produced from this material.

Analysis for C8H9N3O, MG 163:

C.

H

N

Calculated:

58.88

5.56

25.75

Found:

58.65

5.48

25.54

(B) 1-dimethylaminosulfonyl-2-amino-5 (6) -hydroxymethyl-benzimidazole

4.9 g (30 mmol) of 2-amino-5 (6) -hydroxymethylbenzimidazole are dissolved in 40 ml of acetone. 3.0 g (30 mmol) of triethylamine are then added to the acetone solution, after which 4.32 g (30 mmol) of dimethylsulfamoyl chloride are added. The mixture is heated to reflux for about 17 hours. The mixture is poured into 25 ml of water. The aqueous mixture is extracted with chloroform. The chloroform extract is washed in turn with water and saturated sodium chloride solution. The chloroform solution is filtered and dried. Evaporation of the chloroform solution to dryness in vacuo gives 5.5 g (66%) of crude product in the form of an isomeric mixture.

7 g of the above crude isomeric mixture are chromatographed on Woelm silica gel using ethyl acetate as the eluent. After 6 liters of eluent have flowed through the column, the 6-isomer is collected. This gives a yield of 1.02 g of 1-dimethylaminosulfonyl-2-amino-6-hydroxymethylbenzimidazole, which melts at 182-183 ° C. after recrystallization from ethyl acetate-methanol.

s

10th

is

20th

25th

30th

35

40

45

50

ss

60

65

13

617428

Analysis for C10H14N4O3S, MG 270:

C H N

Calculated: 44.43 5.22 20.73 Found: 44.37 5.18 20.44

According to the processes described in Examples 1 to 6, the following compounds are prepared using suitable substituted benzimidazoles as starting materials:

Example 7

l-Dimethylaminosulfonyl-2-amino-5-benzimidazole carbonic acid hydrazide, mp. 229-230 ° C (dec.)

C.

H

N

Calculated:

40.30

4.70

28.20

Found:

40.21

4.54

28.33

Example 8

l-Dimethylaminosulfonyl-2-amino-6-benzimidazole carbonate hydrazide hydrate, mp. 205-206 ° C.

C.

H

N

Calculated:

37.97

5.06

26.58

Found:

38.40

4.41

26.15

Example 9

l-Dimethylaminosulfonyl-2-amino-5-benzimidazole carboxamide hydrate, mp. 208-209 ° C

C.

H

N

Calculated:

39.87

4.98

23.25

Found:

40.05

4.78

22.81

Example 10

l-dimethylaminosulfonyl-2-amino-6-benzimidazole carbox-

amide, m.p. 206-208 ° C

C.

H

N

Calculated:

42.40

4.63

24.72

Found:

43.56

4.53

24.60

Example 11

l-Dimethylaminosulfonyl-2-amino-5-N-ethylbenzimidazole-carboxamide, mp. 155-160 ° C

C H N

Calculated: 46.29 5.50 22.49 Found: 46.54 5.24 21.93

Example 12

l-Dimethylaminosulfonyl-2-amino-6-N-ethylbenzimidazole-carboxamide, mp. 215-216 ° C

C.

H

N

Calculated:

46.29

5.50

22.49

Found:

46.11

5.35

22.25

Example 13

Ethyl 1- (2-thiophene) sulfonyl-2-amino-5 (6) -benzimidazole carboxylate

C.

H

N

Calculated:

47.85

3.73

11.96

Found:

47.67

3.84

11.76

Example 14

Ethyl l- (2-acetamido-4-methylthiazol-5-yl) sulfonyl-2-amino: -5 (6) -benzimidazole carboxylate, mp. 190-202 ° C (dec.)

C.

H

N

Calculated:

45.39

4.02

16.54

Found:

45.52

4.43

15.94

Example 15

Ethyl 1- (2-methylamino-l, 3,4-thiadiazol-5-yl) sulfonyl-2-amino-5 (6) -benzimidazole carboxylate

C H N

Calculated: 40.83 3.69 21.98 Found: 40.59 3.94 21.78

Example 16

Ethyl 1- {N-methyl-N-propylaminosulfonyl) -2-amino-5 (6) -benzimidazole carboxylate, m.p. 140-148 ° C

C.

H

N

Calculated:

49.40

5.92

16.46

Found:

49.30

6.13

16.37

Example 17

Ethyl l-diethylaminosulfonyl-2-amino-6-benzimidazole-carboxylate, mp 142-143 "C"

C.

H

N

Calculated:

49.40

5.92

16.46

Found:

49.73

5.90

16.18

Example 18

Ethyl-1-benzenesulfonyl-2-amino-5 (6) -benzimidazole carboxylate

C.

H

N

Calculated:

55.64

4.38

12.17

Found:

55.86

4.48

12.22

The compounds listed in the following tables are prepared according to the above procedure:

s

10th

is

20th

25th

30th

35

40

45

so

55

60

65

617428

14

Table IV

Other esters of l-dimethylaminosulfonyl-2-amino-5 (6) -benzimidazole carboxylic acids

Analysis (percent)

Example No.

Ester *

Melting point in ° C

c calculates H

N

C.

found H

N

19th

(6) methyl

211-213

44.29

4.73

18.78

45.28

4.72

18.21

20th

(5) ethyl

167-168

46.29

4.86

18.00

46.01

5.05

17.55

21st

(6) ethyl

201-202

46.29

4.86

18.00

45.99

5.04

17.87

22

Propyl

47.84

5.57

17.17

47.62

5.31

16.92

23

(6) -isopropyl

173-175

47.84

5.56

17.17

48.08

5.42

16.96

24th

(6) -Butyl

150-153

49.40

5.92

16.40

49.64

5.98

16.20

25th

(6) -isobutyl

197-198

49.40

5.92

16.46

49.67

5.97

16.56

26

(5) -Neopentyl

157-160

50.83

6.26

15.81

51.06

6.03

15.75

27th

(6) -Neopentyl

196-198

50.83

6.26

15.81

50.99

6.05

15.99

28

(6) -cyclohexyl

180-184

52.44

6.05

15.29

52.67

6.29

15.48

29

Octyl

54.53

7.12

14.13

54.26

6.87

13.85

30th

Cyclohexylmethyl

53.68

6.32

14.74

53.85

6.38

13.71

31

alpha-methylbenzyl

55.66

5.19

14.42

56.83

5.41

13.87

32

Allyl

48.29

4.68

17.33

48.50

4.47

17.30

33

Propargyl

48.59

4.08

17.44

48.32

4.06

17.31

34

Benzyl

54.27

5.02

15.33

54.64

4.95

15.95

: S The number in brackets means that this is an ester isomer, otherwise the ester is a mixture of isomers.

Table V

Esters of 1-dimethylaminosulfonyl-2-acetamido-5 (6) -benzimidazole carboxylic acids

Example No.

Ester®

Melting point in ° C

c calculates H

Analysis (percent) N C

found H

N

35

(5) ethyl

167-168

47.45

5.12

15.81

47.60

5.19

16.03

36

(6) ethyl

201-202

47.45

5.12

15.81

47.28

5.16

15.60

37

Isopropyl

48.90

5.47

15.21

48.92

5.76

15.46

38

(5) -isobutyl

105-108

50.25

5.80

14.65

50.24

5.69

14.89

39

(6) -isobutyl

151-152

50.25

5.80

14.65

50.46

5.68

14.43

40

sec-butyl

50.26

5.76

14.66

49.94

5.60

14.35

41

Cyclobutyl

50.52

5.30

14.73

50.39

5.08

14.56

42

Neopentyl

51.52

6.06

14.14

51.73

5.98

14.29

43

Cyclohexyl

52.93

5.92

13.72

53.04

5.68

13.90

44

(5) -cyclopropylmethyl

109-112

50.79

4.79

14.81

50.58

5.00

14.73

45

(6) -cyclopropylmethyl

146-149

50.79

4.79

14.81

50.55

5.02

14.97

46

1-cyclopropylethyl

51.76

5.62

14.20

51.47

5.40

14.29

47

Cyclohexylmethyl

54.01

6.2 0

13.26

53.94

6.01

13.16

48

(3-methylhyclohexyl) methyl

53.03

6.47

12.83

54.87

6.66

12.68

49

(5) -phenyl

169-170

53.59

4.75

13.89

53.88

4.59

13.61

50

(6) -phenyl

215-220

53.59

4.75

13.89

53.73

5.03

13.79

* The number in brackets means that it is an ester isomer, otherwise the ester is a mixture of isomers.

Example 51

Tert.butyl-1-dimethylsulfonylamino-2-amino-5 (6) benzimidazole carboxylate (A) tert.butyl-3,4-dinitrobenzoate

53 g (0.25 mol) of 3,4-dinitrobenzoic acid, 500 ml of benzene, 65 g (0.51 mol) of oxalyl chloride and 1 ml of pyridine were stirred at room temperature for about an hour. The mixture was heated to 55 ° C to give a homogeneous solution. Then the reaction mixture was evaporated in vacuo leaving an oil, namely 3,4-dinitrobenzoyl chloride.

This crude 3,4-dinitrobenzoyl chloride was dissolved in 500 ml of benzene and 25 ml of pyridine was added to the reaction mixture. Then 22 g (0.3 mol) were tert. Dropped in butanol. The reaction mixture was then refluxed for four hours and filtered. The filtrate was washed successively with dilute acid, dilute base and

Washed water. The washed benzene solution was dried and evaporated under reduced pressure, leaving 33 g of 3,4-dinitrobenzoic acid tert-butyl ester in 49% yield.

Analysis for C11H12N2O6, MG 268:

C.

H

N

Calculated:

49.26

4.51

10.44

Found:

48.95

4.30

10.14

65 (B) 2-amino-5 (6) -benzimidazole carboxylic acid tert-butyl ester

4.2 g (0.02 mol) of tert-butyl 3,4-dinitrobenzoate were dissolved in 95 ml of ethanol with 1 g of a palladium catalyst

15

617428

(5% palladium on activated carbon) hydrogenated for one hour at room temperature. The exothermic reaction gave a maximum temperature of 45 ° C and 85% of the theoretical amount of hydrogen was taken up. The catalyst was filtered off and the filtrate was evaporated under reduced pressure, leaving an oily residue. The crude product (0.017 Moi 3,4-diaminobenzoic acid tert-butyl ester) was taken up in a mixture of 20 ml methanol and 200 ml water. Then 1.8 g (0.017 mol) of cyanogen bromide was allowed to react with the diamino ester and stirred overnight. The aqueous mixture was made basic with 1N sodium hydroxide solution and extracted with ethyl acetate. The extracts were decolorized with carbon and filtered. The solution in ethyl acetate was evaporated in vacuo, leaving 1.5 g (38% yield) of tert-butyl 2-amino-5 (6) -benzimidazole carboxylate.

(C) l-Dimethylaminosulfonyl-2-amino-5 (6) -benzimidazole-carboxylic acid tert-butyl ester

3 g (0.013 mol) of tert-butyl-2-amino-5 (6) -benzimidazole carboxylate, 50 ml of dimethoxyethane, 0.7 g of 50% sodium hydride and 1.9 g of dimethylsulfamoyl chloride were refluxed together for three hours. The reaction mixture was then filtered and the filtrate evaporated under reduced pressure. The residue was treated with water and the mixture extracted with ethyl acetate. The extract was dried over sodium sulfate and evaporated by boiling on a steam bath until crystallization occurred. The mixture was then cooled in an ice bath and the crystalline product which was tert-butyl-1-dimethylsulfamoyl-2-amino-5 (6) -benzimidazole carboxylate was filtered off.

Example 52

l-Cyclohexylsulfonyl-2-aminobenzimidazole-5 (6) -carbonate

To a slurry of 2.5 g (0.012 mol) of 2-amino-5-ethoxycarbonyl-benzimidazole in 100 ml of acetone are added 2 ml of triethylamine with stirring. 2.3 g (0.013 mol) of cyclohexylsulfonyl chloride in 5 ml of acetone are added to the reaction mixture with stirring. The reaction mixture is then refluxed for 18 hours, filtered and evaporated to leave an oil. The oil is left to stand over methanol and slowly crystallizes, giving 1 g of ethyl 1-cyclohexylsulfonyl-2-aminobenzimidazole-5 (6) -carboxylate.

Analysis for C16H21N3O4S, MG 351:

C.

H

N

Calculated:

54.70

5.98

11.96

Found:

54.33

5.86

11.88

Example 53

l-cyclopentylsulfonyl-2-aminobenzimidazole-5 (6) -carbon-

Acid ethyl ester 3.7 g (0.018 mol) of 2-amino-5-ethoxycarbonylbenzimidazole, 2.5 g of triethylamine, 3.1 g (0.018 mol) of cyclopentylsulfonylchloride and 100 ml of acetone were reacted according to Example 52, l-cyclopentylsulfonyl-2 -aminobenzimidazole-5 (6) -carboxylic acid ethyl ester were formed. Ethyl acetate was added to this crude product. The crystals obtained were filtered off, washed with water and ether and dried, and 1 g of 1-cyclopentylsulfonyl-2-amino-benzimi-dazole-6-carboxylic acid ethyl ester, mp. 179 to 180 ° C., dec.

Analysis for C15H19N3O4S, MG 337:

C H N

Calculated: 53.40 5.68 12.45 Found: 53.51 5.86 12.18

1 g of ethyl 1-cyclopentylsulfonyl-2-aminobenzimidazole-5-carbonate was isolated from the mother liquor.

Analysis for C15H19N3O4S • H2O, MG 355:

C.

H

N

Calculated:

50.70

5.92

11.83

Found:

50.78

5.92

11.78

Example 54

1-cycloheptylsulfonyl-2-aminobenzimidazole-5 (6) -carbon-

Acid ethyl ester 3.7 g (0.018 mol) of 2-amino-5-ethoxycarbonylbenzimidazole in 100 ml of acetone, 2.5 ml of triethylamine and 3.6 (0.018 mol) of cycloheptylsulfonyl chloride were reacted according to the procedure of Example 52. The salt was filtered and the filtrate evaporated on a steam bath and then cooled. 750 mg of l-cycloheptylsulfonyl-2-aminobenzimidazole-5 (6) -carboxylic acid ethyl ester were obtained.

Analysis for C17H23N3O4S, MG 365:

C.

H

N

Calculated:

55.87

6.34

11.48

Found:

55.98

6.10

11.43

Example 55

l-Pyrrolidylsulfamoyl-2-aminobenzimidazole-5 (6) -carbonate

A slurry of 10 g (0.05 mol) of 2-amino-5-ethoxycarbonylbenzimidazole in 40 ml of acetone and 10 ml of triethylamine was added to 8.5 g of pyrrolidylsulfamoyl chloride in 10 ml of acetone. The reaction mixture was refluxed for 48 hours and then filtered. The product was washed with water and dried. There were 12 g (65% yield) l-pyrrolidylsulfamoyl-2-amino-5 (6) -ethoxycarbon-ylbenzimidazole, mp. 189 to 192 ° C.

Example 56

l-piperidinosulfamoyl-2-amino-5-ethoxycarbonyl-benzimidazole

10 ml of triethylamine were added to 10 g (0.05 mol) of 2-amino-5-ethoxycarbonylbenzimidazole in 300 ml of acetone with stirring. Then 9.2 g (0.05 mol) of pipidinosulfamoyl chloride were added to the solution. The reaction mixture was refluxed for 72 hours, then cooled and filtered. The filtrate was concentrated under vacuum and the residue was triturated with methanol and then washed with methanol to give 6.2 g of l-piperidinosulfamoyl-2-amino-5-ethoxycarbonylbenzimidazole.

Analysis for C15H19N4O4S, MG 351:

C H N

Calculated: 51.27 5.45 15.94 Found: 51.04 5.25 15.72

5

10th

15

20th

25th

30th

35

40

45

50

55

60

65

617428

16

Example 57

1-morpholinosulf amoyl-2-amino-5 (6) -ethoxycarbonyl-benzimidazole

10 g (0.05 mol) of 2-amino-5 (6) -ethoxycarbonylbenzimidazole, 300 ml of acetone, 9.2 g (0.05 mol) of morpholinosulfamoyl chloride and 10 ml of triethylamine were reacted according to the procedure of Example 56 . 1.7 g of 1-morpholinosulfamoyl-2-amino-5 (6) -ethoxycarbonylbenzimidazole were obtained, m / e 354, 309, 203.

Analysis for C14H18N4O5S, MG 354:

C.

H

N

Calculated:

47.45

5.12

15.81

Found:

48.00

5.00

14.06

Example 58

l-dimethylsulfamoyl-2-methylamino-6-ethoxycarbonyl-benzimidazole

500 ml of 50% sodium hydride was added to a slurry of 2.2 (0.01 mol) of 2-methylamino-6-ethoxycarbonyl-benzimidazole in 50 ml of dry tetrahydrofuran and 1 ml of dry dimethylformamide, the reaction mixture was kept at room temperature under nitrogen for 20 minutes touched. 1.5 g of dimethylsulfamoyl chloride in 10 ml of tetrahydrofuran were added to the solution and the mixture was refluxed for 16 hours, cooled and 5 ml of water were added. The mixture was evaporated under reduced pressure, the remaining oil triturated with water, the water decanted, the product washed with n-hexane and finally triturated with methanol. 700 mg of crystalline 1-dimethylsulfamoyl-2-methylamino-6-ethoxycar-bonylbenzimidazole of mp 127 to 132 ° C. could be filtered off.

Analysis for C13H18N4O4S, MG 326:

C H N

Calculated: 47.84 5.56 17.17 Found: 48.09 5.39 16.91

Example 59

l-Dimethylsulfamoyl-2-amino-5 (6) -ethoxycarbonyl-methylbenzimidazole 5 g (0.023 mol) of 2-amino-5-ethoxycarbonylmethylbenzimi-dazole, 50 ml of acetone, 3.5 ml of triethylamine and 3.3 g of dimethylsulfamoyl chloride were added after the Example 52 operation implemented. The mixture was refluxed for 16 hours and the precipitate formed was washed with water. 1.4 g of l-dimethylsulfamoyl-2-amino-5-ethoxycarbonylmethylbenzimidazole were obtained, mp. 185 to 187 ° C.

Analysis for C13H18N4O4S, MG 326:

C H N

Calculated: 47.85 5.52 17.18 Found: 48.34 5.50 16.92

The filtrate was then evaporated under reduced pressure to give 1.8 g of l-dimethylsulfamoyl-2-amino-5 (6) -ethoxycarbonylmethyl-benzimidazole.

Analysis for C13H18N4O4S, MG 326:

C H N

Calculated: 47.85 5.52 17.18

The overall yield of the products obtained was 79%. Example 60

1-Dimethylsulfamoyl-2-amino-5 (6) - (l-methoxycarbonyl-ethyl) benzimidazole

2-Amino-5- (l-methoxycarbonylethyl) benzimidazole was dissolved as a crude oil in 20 ml of acetone. Were the solution

Given 0.6 ml of triethylamine and 0.7 ml of dimethylsulfamoyl chloride. The mixture was refluxed for 24 hours, cooled to room temperature, filtered to remove the precipitated triethylamine hydrochloride, evaporated with acetone and suction filtered to leave a solid. This was recrystallized from methanol and 600 mg of 1-dimethylsulfamoyl-2-amino-5 (6) - (l-methoxycarbonylethyl) benzimidazole, mp 155 to 159 ° C., were obtained in 25% yield.

Analysis for C13H18N4O4S, MG 326:

C.

H

N

Calculated:

47.84

5.56

17.17

Found:

47.58

5.53

16.91

Example 61

l-dimethylsulfamoyl-2-amino-5-hydrazinocarbonyl-

benzimidazole (and corresponding 6-isomer) To a solution of 3 g of 1-dimethylsulfamoyl-2-amino-5 (6) -ethoxycarbonylbenzimidazole in 50 ml of methanol was added 6 ml of 85% hydrazine monohydrate. The solution was stirred at room temperature overnight and then refluxed for four days. The solution was filtered hot and 200 mg of 1-dimethylsulfamoyl-2-amino-5-hydrazinocarbonylbenzimidazole were obtained, mp. 229 to 230 ° C., decomposition. The solution was then allowed to cool and the product which then precipitated was filtered off, as was a second addition from the filtrate. 550 mg of 1-dimethylsulfamoyl-2-amino-6-hydrazinocarbonylbenzimidazole, mp. 205 to 206 ° C., decomposition were obtained.

Example 62

l-Dimethylsulfamoyl-2-amino-5 (6) - (N-methoxy-carboxamido) -benzimidazole To 6 g (0.018 mol) of l-dimethylsulfamoyl-2-acetamidobenz-imidazole-5 (6) -carboxylic acid in 10 ml of dimethylformamide 3.6 g of carbonyldiimidazole were added and the mixture was stirred for 15 minutes. 1.6 g of N-methoxyamine hydrochloride in 5 ml of dimethylformamide were added to the solution. The mixture was then stirred at room temperature overnight. The solution was then concentrated by pouring it into water and extracting with ethyl acetate, and an oil was obtained. For further purification, the oil was brought to 200 g of silica gel and eluted with ethyl acetate to give 1-dimethylsulfamoyl-2-amino-5 (6) - (N-methoxycarboxamido) benzimidazole. This compound appeared to contain some water and to easily split off the acetyl group, since the presence of an acetyl group could not be detected in the KMR spectrum, m / e 313, 298, 267.

Example 63

l-Dimethylsulfamoyl-2-amino-5 (6) -cyanobenzimidazole 1.2 g of a 50% dispersion were added to a solution of 4 g (0.025 mol) of 2-amino-5 (6) -cyano-benzimidazole in 50 ml of tetrahydrofuran of sodium hydride added with stirring. 3.6 g of dimethylsulfamoyl chloride was further added to the solution and the solution was refluxed for twenty hours. The reaction mixture was cooled, filtered and concentrated in vacuo using a rubber

s

10th

15

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25th

30th

35

40

45

50

55

60

65

17th

like a residue. This was triturated with n-hexane, mixed with 100 ml of hot methanol and recrystallized from 350 ml of methanol. After concentrating to 100 ml, 3.5 g of 1-dimethylsulfamoyl-2-amino-5 (6) -cyanobenzimidazole were obtained in 53% yield, m / e 265.157. s

Analysis for C10H11N5O2S, MG 265:

C.

H

N

Calculated:

45.27

4.18

26.40

Found:

45.46

4.45

26.12

Example 64 15

l-dimethylsulfamoyl-2-amino-5-methylsulfonyl-benzimidazole

10.5 g (0.05 mol) of 2-amino-5-methylsulfonylbenzimidazole in 300 ml of acetone, 7.2 g of dimethylsulfamoyl chloride and 10 ml of triethylamine were reacted according to the procedure of Example 56-20. The solution was refluxed for 120 hours, cooled and filtered to give 5.5 g of 1-dimethylsulfamoyl-2-amino-5-methylsulfonylbenzimidazole, mp. 205 to 206 ° C.

617428

Analysis for C10H14N4O4S2, MG 318:

C.

H

N

Calculated:

37.73

4.43

17.60

Found:

38.00

4.41

17.34

Example 65

l-dimethylsulfamoyl-2-amino-5-trifluoromethyl-benzimidazole

10 g (0.05 mol) of 2-amino-5-trifluoromethylbenzimidazole in 300 ml of acetone, 7.2 g of dimethylsulfamoyl chloride and 10 ml of diethylamine were reacted according to the procedure of Example 56. The solution was refluxed for 42 hours and filtered. 3.4 g of 1-dimethylsulfamoyl-2-amino-5-trifluoromethylbenzimidazole were obtained, mp. 203 to 205 ° C., decomposition.

Analysis for C10H11N4F3O2S, MG 308:

C.

H

N

S

Calculated:

38.96

3.60

18.17

10.40

Found:

39.10

3.80

18.04

10.20

B

Claims (13)

617428 2. The method according to claim 1 for the preparation of ethyl 1-isopropylsulfonyl-2-amino-5 (6) -benzimidazole-carboxylate, characterized in that ethyl-2-amino-5 (6) -benzimidazole-carboxylate is reacted with isopropylsulfone-vinyl chloride . 2nd PATENT CLAIMS 1. Process for the preparation of new 1-sulfonyl-benz-imidazoles of the formula I. SO "R R 3. The method according to claim 1 for the preparation of ethyl 1-dimethylaminosulfonyl-2-amino-5 (6) -benzimida-zolcarboxylat, characterized in that ethyl-2-amino-5 (6) -benzimidazole carboxylate is reacted with dimethylaminosulfonyl chloride . 3rd wherein Ri for Ci-Cs-alkyl, methylcyclopropyl, methylcyclohexyl, Cs-Cz-cycloalkyl, phenyl, furyl, thienyl, thiazol-2-yl, 2-acetamido-4-methylthiazol-5-yl, l, 3,4-thiadiazol- 2-yl, 2-methyl-l, 3,4-thiadiazol-5-yl, 2-methylamino-l, 3,4-thiadiazol-5-yl or R4R5N—, where the substituents R4 and Rs are independently Ci C3-alkyl or together with the nitrogen atom to which they are attached mean pyrrolidino, piperidino or morpholino. R2 is hydrogen, methyl, amino, acetamido or methylamino, R? for Ci-C8-alkoxycarbonyl, allyloxycarbonyl, propargyl-oxycarbonyl, (C3-C7-cycloalkyl) oxycarbonyl, (C3-C7-cyclo-alkyl) methyloxycarbonyl, l- (C3-C7-cycloalkyl) ethyloxycarbon-yl, benzyloxycarbonyl, alpha- Methylbenzyloxycarbonyl, phenoxycarbonyl, Ci-Cs-alkoxycarbonylmethyl, l- (Ci-Cs-alkoxycarbonyl) ethyl, hydrazinocarbonyl, carboxy, carboxy-amido, N- (Ci-C4-alkyl) carboxyamido, N- (Ci-C4-alkoxy) car boxamido, hydroxymethyl, cyano, methylsulfonyl or trifluoromethyl and the substituent R3 is in position 5 or 6, characterized in that a tautomeric benzimidazole of the formula II with a sulfonyl chloride of the formula R1SO2CI, in which the substituents R 1, R 2 and R 3 have the meanings given above. 4. The method according to claim 1 for the preparation of isopropyl-1-dimethylaminosulfonyl-2-amino-5 (6) -benz-imidazole carboxylate, characterized in that isopropyl-2-amino-5 (6) -benzimidazole carboxylate is reacted with dimethylaminosulfonyl chloride . 5. The method according to claim 1 for the preparation of neopentyl-l-dimethylaminosulfonyl-2-amino-5 (6) -benz-imidazole carboxylate, characterized in that Neopentyl-2-amino-5 (6) -benzimidazole carboxylate with dimethylaminosulfonyl chloride. 6. The method according to claim 1 for the preparation of cyclohexyl-l-dimethylaminosulfonyl-2-amino-5 (6) -benz-imidazole carboxylate, characterized in that cyclohexyl-2-amino-5 (6) -benzimidazole carboxylate is reacted with dimethylaminosulfonyl chloride . 7. The method according to claim 1 for the preparation of ethyl 1- (N-methyl-N-ethylaminosulfonyl) -2-amino-5 (6) -benzimidazole carboxylate, characterized in that that one reacts ethyl 2-amino-5 (6) -benzimidazole carboxylate with N-methyl-N-ethylaminosulfonyl chloride. 8. The method according to claim 1 for the preparation of ethyl 1- (N-methyl-N-propylaminosulfonyl) -2-amino-5 (6) -benzimidazole carboxylate, characterized in that that one reacts ethyl-2-amino-5 (6) -benzimidazole carboxylate with N-methyl-N-propylaminosulfonyl chloride. 9. The method according to claim 1 for the preparation of ethyl-l-diethylaminosulfonyl-2-amino-5 (6) -benzimida-zolcarboxylate, characterized in that ethyl-2-amino-5 (6) -benzimidazole carboxylate is reacted with diethylaminosulfonyl chloride . 10. The method according to claim 1 for the preparation of ethyl-l-benzenesulfonyl-2-amino-5 (6) -benzimidazole car-boxylate, characterized in that ethyl-2-amino-5 (6) -benzimidazole carboxylate is reacted with benzenesulfonyl chloride . 11. The method according to any one of the preceding claims, characterized in that obtained position isomer ren mixtures, in which the substituent Rs is in the 5- and 6-position, separated into the isomers. 12. The method according to claim 1 for the preparation of compounds of the formula I in which R3 is N- (Ci to C4-alkoxy) carboxamido, characterized in that a compound of the formula I obtained in which R3 = -COOH is obtained, reacted with an appropriate alkoxyamine. 13. The method according to claim 1 for the preparation of compounds of the formula I in which R3 is hydrazinocarbonyl, characterized in that a compound of the formula I obtained in which R3 = -COOC2H5 is reacted with hydrazine.