CS202556B2 - Process for preparing 1-sulphonylbenzimidazoles substituted on carbonyl group - Google Patents

Description

(54) A method for producing 1-sulfonylbenzimidazoles substituted on a carbonyl group

The incidence of upper respiratory tract viral diseases is currently high; it has been established that in the United States alone, there are almost a trillion diseases per year. Statistics in the UK [(Tyrell and Bynoe, Lancet 1, 16, 1966) show that 74% of people with upper respiratory tract infection were infected with rhinoviruses, although more than 80 strains of rhinoviruses are known, vaccination is almost impractical, so chemotherapy is likely to be the only possible solution.

The ability of chemicals to inhibit the growth of viruses in vitro can be demonstrated using tissue cultures that do not produce virus-induced plaques as described in Siminoff, Applied Microbiology, 9 (1), 66 (1961).

Some 1-dimethylaminosulfonyl-2-aminobenzimidazoles having antifungal activity have been described in US Patent No. 3,853,908.

The invention relates to a process for the production of novel benzimidazole compounds which inhibit the growth of viruses, in particular rhinoviruses, polioviruses, Cocxsackie, echo and Mengo viruses.

SUMMARY OF THE INVENTION The present invention provides a process for the preparation of novel 1-sulfonylbenzimidazoles substituted on the carbonyl group of Formula I

where

R is alkyl of 1 to 4 carbon atoms, cycloalkyl of 5 to 7 carbon atoms, thienyl, or the group -NR 3 R 4 in which R 5 and R 4, the same or different, are alkyl of 1 to 3 carbon atoms,

R 1 represents a hydrogen atom

R2 represents a hydrogen atom, an alkyl of 1 to 4 carbon atoms, a phenyl or a halophenyl,

Z represents an oxygen atom, a group

20255B

202536 is in the 5 or 6 position and n is 1, wherein the compound of formula II is reacted

wherein R 2 and n are as defined above, with a sulfonyl chloride of formula III

RSOaCl (III), wherein R is as defined above, in the presence of an organic solvent and optionally a base at room temperature to reflux.

The term "tautomeric benzimidazole" refers to benzimidazole, which may be substituted on any nitrogen atom by a hydrogen atom. The benzimidazole unsubstituted at the nitrogen atom and substituted in the 5-position of the benzene ring has the corresponding tautomeric form in which the same substituent is in the 6-position. The mixture of these isomers may be designated 5 (6). As a result of this tautomerism, the reaction of 5 (6) -substituted benzimidazole with the sulfonyl chloride of formula III results in an isomeric mixture of 5 (6J-substituted sulfonylbenzimidazoles).

The term "thienyl" refers to a thiophene moiety bound at the 2 or 3 position.

The term "C 1 -C 4 alkyl" refers to straight or branched chain aliphatic radicals of 1 to 4 carbon atoms, namely methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl. The term "alkyl of 1 to 4 carbon atoms" includes the term "alkyl of 1 to 3 carbon atoms".

The term "C 1 -C 4 alkylcarbinol" refers to a straight or branched chain C 1 -C 4 aliphatic alcohol derived from a C 1 -C 4 alkyl group as defined above.

The term "cycloalkyl of 5 to 7 carbon atoms" refers to a saturated alicyclic ring of 5 to 7 carbon atoms such as cyclopentyl, cyclohexyl, 1-, 2-, 3- or 4-methylcyclohexyl and cycloheptyl.

The term "halophenyl" refers to chlorophenyl or bromophenyl, wherein the substituent is at any position on the phenyl ring.

Preferred reactants are benzimidazole derivatives with 5 (6) -substituents that do not react with the sulfonyl chloride under the reaction conditions. Benzimidazole derivatives and sulfonyl chloride are generally used in approximately equimolar amounts, although a small excess of either may be used. The reaction can be carried out in a wide variety of non-reactive solvents such as acetone, tetrahydrofuran, tertiary amides such as Ν, Ν-dimethylformamide and chlorinated hydrocarbons such as dichloromethane, dichloroethane, and chloroform.

The reaction medium may also contain a base as an acid binding agent. Examples of a suitable base for this use are pyridine, triethylamine, N-methylformoline, sodium hydrogen carbonate and sodium hydride. A preferred solvent is acetone containing triethylamine or tetrahydrofuran with dimethylformamide and containing sodium hydride as the base.

The reaction is carried out at room temperature to the reflux temperature of the solvent used. Preferably, the reaction is carried out at reflux, since in this case it takes only 1 to 48 hours.

The product of the reaction is a 1-sulfonylbenzimidazole derivative, hereinafter referred to as the sulfonylbenzimidazole derivative. The product can be isolated by reaction filtration. and concentrating the filtrate to crystallize. The reaction mixture can also be evaporated to dryness and the residue dissolved in a suitable solvent such as acetone or methanol to separate and remove insoluble material.

The solution containing the sulfonylbenzimidazole derivative is concentrated to crystallize or re-evaporated to dryness and the second residue is then dissolved, for example in methanol, from which the resulting product is crystallized.

Reaction of the tautomeric benzimidazole derivative and the sulfonyl chloride usually results in a mixture of 5- and 6-substituted sulfonylbenzimidazole, the isomer ratio usually being 1: 1. Isomers can be separated by fractional crystallization or column chromatography. First, the 6-isomer usually crystallizes. For example, when 2-amino-5-benzimidazolecarboxylate is reacted with dimethyl chloride in triethylamine-containing acetone, ethyl-1-dimethylaminosulfonyl-2-amino-6-benzimidazolecarboxylate crystallizes as the first solution from the reaction mixture; 1-dimethylaminosulfonyl-2-amino-5-benzimidazolecarboxylate and the remainder 6-isomers. Isomers can be identified by nuclear magnetic resonance in the proton region of the phenyl group (7.0 to 8.3 ppm).

Certain compounds of Formula I may be prepared by chemical methods such as acylation, oxidation or reduction of the corresponding sulfonylbenzimidazole precursor. When the reaction is carried out on a precursor which is an isomeric mixture of sulfonlylbenzimidazoles,

By 202536, the isomeric products may be separated from one another by traction crystallization or chromatography.

It will be appreciated that the individual chemical processes may be advantageously performed at some stage in the synthesis of the resulting materials. The benzimidazole reactant can be chemically altered and then reacted with the appropriate sulfonyl chloride to give the resulting sulfonylbenzimidazole. The sulfonylbenzimidazole intermediate can also be chemically modified to the desired end product. Suitable benzimidazole reactants are especially those whose substituents can be converted to the desired 5- (6-substituents) before or after reaction with the corresponding sulfonyl chloride. Particularly suitable reactants are 2-substituted-5 (6) -benzimidazolecarboxylic acid ethyl ester since the ester function can be used to produce other intermediates which can then be easily converted to the end products.

Ethyl esters of 1-sulfonyl-2-substituted-5 (6) -benzimidazolecarboxylic acids can be chemically reduced to give the corresponding hydroxymethyl intermediates. For example, ethyl 1-dimethylaminosulfonyl-2-acetamido-5 (6) -benzimidazolecarboxylate bis-2- (2-methoxyethoxy) aluminum hydride in tetrahydrofuran can be reduced to give 1-dimethylaminosulfonyl-2-acetamido-5 (6-hydroxymethylbenzimidazole). A more preferred procedure is the reaction of the sulfonyl chloride RSO 2 with the corresponding substituted 2-5 (6) -hydroxymethylbenzimidazole The desired 5- (6-hydroxymethylbenzimidazole) can be obtained from the corresponding ethyl 2-substituted-5 (6) -benzimidazolecarboxylic acid by sodium bis (2-methoxyethoxy) aluminum hydride. In a preferred process for producing large amounts of hydroxymethylsulfonylbenzimidazole intermediates starting from 4-chloro-3-nitrobenzyl alcohol, benzyl alcohol is reacted with ammonia to form 4-amino-3-nitrobenzyl alcohol and the nitroalcohol is catalytically hydrogenated to form 4-chloro-3-nitrobenzyl alcohol. The phenylenediamine is closed with n-hydroxymethyl-o-phenylenediamine and a ring to form the desired 2-substituted-5- (6H-hydroxymethylbenzimidazole intermediate) in a known manner.

Usually, the 5 (6'-hydroxymethylsulfonylbenzimidazole derivatives can be converted to the corresponding 5 (6'-formyl derivatives). The oxidation of the hydroxymethylcarbinol function to give the carboxaldehyde derivative with inhibitory properties for viruses is completely unexpected.

Sulfonylbenzimidazolecarboxaldehydes in which R2 is hydrogen can be prepared from the corresponding 1-sulfonyl-2-substituted-5- (6'-hydroxymethylbenzimidazole by oxidation of the hydroxylmethyl group with Jones reagent, i.e. a solution of chromic acid and sulfuric acid in water, for example using 1- dimethylaminosulfonyl-2-amino-5 (6 H -hydroxymethylbenzimidazole) was oxidized with Jones reagent to give 1-dimethylaminosulfonyl-2-amino-5 (6 H -methylbenzimidazole).

These reactions of the carbonyl group are shown in Reaction Scheme I.

Reaction Scheme I

(6J-Ketosulfonylbenzimidazole compounds in which Z is oxygen) can be prepared from the corresponding 5 (6J-ketobenzimidazoles by reaction with sulfonyl chloride RSO 2 Cl. These benzimidazoles can be prepared from the corresponding keto-o-phenylenediamine in a known manner. No. 93,791 describes a process for preparing keto-o-phenylenediamines of the general formula

wherein R 2 is lower alkyl, cycloalkyl, phenyl, optionally substituted with halogen, lower alkyl or lower alkoxy.

The method consists in ammonolysis and reduction of 4-halo-3-nitrophenyl ketone, which is prepared by Friedel-Crafts reaction.

4) halogen-3-nitrobenzoyl chloride with the appropriate hydrocarbon; or 2) halobenzene with the appropriate acid chloride followed by aromatic nitration. These methods are used to obtain keto-o-phenylenediamines in which R 2 in the above formula may also mean cycloalkyl of 3 to 6 carbon atoms. Ketobenzimidazoles can also be prepared from acetanilide by Friedel-Crafts aceylation with the appropriate C 2 -C 8 alkanoic acid or C 3 -C 6 cycloalkylcarboxylic acid derivative in the cycloalkyl moiety. The resulting 4-ketoacetanilide is nitrated to give 2-nitro-4-ketoacetanilide. This acetanilide is then hydrolyzed to 2-nitro-4-ketoaniline. The nitroaniline is catalytically hydrogenated to 4-keto-o-phenylenediamine, which is ring-closed to give 2-substituted 5- (6'-ketobenzimidazole. 5 (6) -Ketosulfonylbenzimidazole can be obtained essentially as follows. 4-Propionylacetanilide is nitrated at 0 ° C to 2-nitro-4-propionylacetanilide which is hydrolyzed and catalytically hydrogenated to 4-propionyl-o-phenylenediamine The phenylenedlamine is reacted with cyanogen bromide to give 2-amino-5 (6) -propionylbenzimidazole. in reaction with dimethylsulfamoyl chloride to give 1-dimethylaminosulfonyl-2-amino-5 (6) -propionylbenzimidazole, but the ketocarbonyl function is less reactive than the carboxyaldehyde function. between a carbon and a nitrogen atom.

The benzimidazole compounds which are the starting materials for carrying out the process according to the invention can be obtained by a number of known methods. The preparation of a variety of benzimidazoles is well described in Weissberger's The Chemistry of Heterocyclic Compounds, Imidazole and Its Derivatives, Interscience Publishers Co., New York., 1953. 2-Aminobenzotimidazole derivatives can be obtained by cyclization of the appropriate o-phenyldiamine with cyanogen bromide as described in Buttle et al., Bio. Chem. J. 32, 1101 (1938), and British Patent No. 551,524.

Of the sulfonyl chlorides which are preferred reactants, methanesulfonyl chloride (mesyl chloride), isopropylsulfonyl chloride, dimethylsulfamoyl chloride and 2-thiophenesulfonyl chloride are commonly supplied. Additional C 1 -C 4 alkylsulfonyl chlorides and C 5 -C 7 cycloalkylsulfonyl chloride may be obtained by chlorination of the corresponding alkylthiol or reaction sulfuryl chloride with sodium alkyl sulfonate derived from the corresponding carbinol and sulfuric acid.

Ν, Ν-Dialkylsulfamoyl chlorides can be obtained according to the method of Bindely et al., J. Am. Chem. Soc. 61, 3250 (1939) by reaction of a secondary amine salt with sulfuryl chloride. Alternatively, they can be obtained by reacting the chloramine of formula

R3R4N-Cl with sulfur dioxide at a temperature of -5 to 30 ° C. The chloramine derivatives are obtained by reacting the corresponding secondary amine with antimony chloride, sodium hypochlorite or sulfuryl chloride.

Ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butylsulfonyl chloride and, in addition, cyclopentyl, cyclohexyl and cyclohexyl cycloheptylsulfonyl chloride are further examples of sulfonyl chlorides which can be used to react with benzimidazole compounds.

Other useful sulfamoyl chlorides are diethyl-, dipropyl-, Ν-methyl-N-ethyl-, N-methyl-N-propyl-, Ν-ethyl-N-propyl-, N-methyl-Ν-isopropyl-, N-ethyl- N-isopropyl-, N-propyl-N-isopropyl- and dilsopropylsulfamoyl chlorides.

For uniformity of nomenclature, sulfonylbenzimidazoles will be called sulfonyl derivatives. For example, the product of the reaction between dimethylsulfamoyl chloride and 2-amino-5-benzoylbenzimidazole is called 1-dimethylaminosulfonyl-2-amino-5 (6) -benzoylbenzimidazole and not 1-dimethylsulfamoyl-2-amino-5 (6) -benzoylbenzimidazole.

Preferred sulfonylbenzimidazoles are those compounds of formula I wherein R is isopropyl or dimethylamino, R 1 is hydrogen, R 2 is phenyl, hydrogen, propyl or p-chlorophenyl, n = 1 and Z is C 1 -C 4 alkoxyimino or oxygen .

Examples of esters and hydroxymethyl intermediates for the preparation of the compounds of formula I are:

ethyl 1-isopropanesulfonyl-2-amino-5 (6) -benzimidazolecarbonyllate, ethyl 1-cyclohexanesulfonyl-2-amino-5 (6) -benzimidazolecarboxylate, ethyl 1- (N-ethyl-N-propylaminosulfonyl) - 2-amino-5 (6) -benzimidazole carboxylate,

1-cyclopropanesulfonyl-2-amino-5 (6) -hydroxymethylbenzimidazole and 1-diethylaminosulfonyl-2-amino-5 (6) -hydroxymethylbenzimidazole.

Examples of the 5 (6) -formylsulfonylbenzimidazoles and their derivatives of formula I include the following:

1-butanesulfonyl-2-amino-5 (6) -formylbenzimidazole,

1-isopropanesulfonyl-2-amino-5 (6) -formylbenzimidazole,

Examples of 5 (6) -ketosulfonylbenzimidazoles and their derivatives of formula I include the following:

1-diethylaminosulfonyl-2-amino-5 (6) -pentamoylbenzimidazole,

1-dimethylaminosulfonyl-2-amino-5 (6) -cyclopropylcarbonylbenzimidazole,

1-Diethylaminosulfonyl-2-amino-5 (6) -cyclopropylcarbonylbenzimidazole.

An example of the 5 (6) -hydroxysulfonylbenzimidazoles and their esters of formula I may be the following compound:

1-ethanesulfonyl-2-amino-5 (6'-hydroxybenzimidazole).

The following examples describe the practice of the process of the invention, starting materials, intermediates and products of formula I. The term "m / e" used in the product characteristic refers to the ion ratio as it appears in the mass spectrum of the product relative to the starting material used. Usually these values correspond to the molecular weights of the major peaks.

Example 1

140 g (0.68 mol) of ethyl 2-amino-5- (6'-benzimidazocarboxylate) were stirred in 500 ml of acetone and 77 ml of triethylamine and 100 g of dimethylsulfamoyl chloride in solution in 100 ml of acetone was added via dropping funnel while stirring the reaction mixture. The reaction mixture is then heated at reflux for 100 hours, then filtered hot to give solid A. The filtrate is allowed to cool to give crystalline solid B. Solids A and B are combined, Wash with water to remove triethylamine hydrochloride and then dissolve in

1.5 liters of hot absolute ethanol. The hot ethanol solution was filtered to remove insoluble material. The ethanol filtrate was allowed to cool to crystallize the product. 23 g of ethyl 1-dimethylaminosulfonyl-2-amino-6-benzimidazolecarboxylate of melting point 215 DEG-217 DEG C. are thus obtained.

For C12H16N4O4S, mass 312 calculated: 46.14% C, 5.16% H, 17.94% N;

Found: 45.87% C, 5.05% H, 18.21% N.

The ethanol filtrate was evaporated in vacuo to a small volume to give 15 g of the 5-isomer, ethyl 1-dimethylaminosulfonyl-2-amino-5-benzimidazolecarboxylate, m.p. 167-168 ° C. This 5-isomer was characterized by NMR spectrum and elemental analysis. The total yield of the product was 38 g (18%).

By the method of Example 1, the other derivatives listed in Examples 2 to 8 are summarized in the following table.

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Example 9

A) 2-Amino-5 (6) -hydroxymethylbenzimidazole

24.6 g of ethyl 2-amino-5 (6) -benzimidazole carboxylate are suspended in 600 ml of tetrahydrofuran under a nitrogen atmosphere. 96 ml (0.36 mol) of sodium bis (2-methoxyethoxy) aluminum hydride (RED-AL) in 400 ml of tetrahydrofuran are then added dropwise to the reaction mixture while stirring so that the temperature of the reaction mixture does not exceed 35 ° C. The mixture was filtered, the filtrate was evaporated to dryness in vacuo and the foamed residue was treated with 150 ml of ethyl acetate and 200 ml of water. The filtrate was evaporated in vacuo to give an additional solid, yielding a total of 12.3 g of crude 2-amino-5 (6) -hydroxymethylbenzimidazole in 65% yield. isomeric mixtures of the product.

For C8H9N3O, (163) calculated: 58.88% C, 5.56% H, 25.75% N; Found:% C, 58.65;% H, 5.48;% N, 25.54.

B) 1-Dimethylaminosulfonyl-2-amino-5 (6) -hydroxymethylbenzimidazole mmol, 4.9 g of 2-amino-5 (6) -hydroxymethylbenzimidazole are dissolved in 40 ml of acetone and 30 mmol, 3.03 g of triethylamine. To the acetone solution was added 4.32 g (30 mmol) of dimethylsulfamoyl chloride, refluxed for 17 hours, then poured into 25 mL of water, extracted with chloroform, and the chloroform extract was washed sequentially with water and a saturated solution. The chloroform solution was filtered and freed from water, and the chloroform was evaporated to dryness in vacuo to give the crude product as a mixture of isomers in 5.5 g (66% yield).

g of the crude isomeric product is chromatographed on silica (Woelm silica gel), eluting with ethyl acetate. The 6-isomer is collected after passing 6 liters of eluent. Yield: 1.02 g of 1-dimethylaminosulfonyl-2-amino-6-hydroxymethylbenzimidazole, m.p. 182-183 ° C, after recrystallization from ethyl acetate-methanol.

For C10H14N4O3S (270) calculated: 44.43% C, 5.22% H, 20.73% N; Found: C, 44.37; H, 5.18; N, 20.44.

Example 10

4) 4-Amino-4-nitrobenzyl alcohol g (0.27 mole of 4-chloro-3-nitrobenzyl alcohol, 250 mL of methanol and 200 mL of liquid ammonia) was placed in a cold autoclave. The autoclave was sealed and heated to 150 degrees Celsius. After cooling the autoclave, the autoclave is opened and the reaction mixture is evaporated in vacuo, the residue is treated with ether and the ethereal solution is filtered to separate ammonium chloride, and the filtrate is evaporated in vacuo to give a solid which is recrystallized from the mixture. absolute ethanol and ethyl acetate to give 4-amino-3-nitrobenzyl alcohol (23.6 g, 52%), mp 100-101 ° C.

For C7H8N2O3 (168) calculated: 50.00% C, 4.80% H, 16.66% N; Found: C, 49.72; H, 4.56; N, 16.44.

B) 3,4-Diaminobenzyl alcohol g (0.035 mole) of 4-amino-3-nitrobenzyl alcohol, 95 ml of tetrahydrofuran and 0.5 g of Raney nickel is hydrogenated at 20 psi at room temperature until 3 moles of hydrogen are absorbed. The catalyst was filtered off and the filtrate was evaporated in vacuo to give 3,4-diaminobenzyl alcohol (4.83 g, 82% yield), m.p. 74-75 ° C.

For C7H10N2O (138) calculated: 60.85% C, 7.30% H, 20.28% N; found: 60.90% C, 7.15% H, 19.99 ® / ₀ N.

C) 2-Amino-5 (6) -hydroxymethylbenzimidazole (0.014 mol) 3,4-diaminobenzylalcohol was dissolved in 40 ml methanol. A solution of 1.6 g (0.014 mol) of cyanogen bromide in 10 ml of methanol was added. After standing overnight at room temperature, the reaction mixture was evaporated to dryness in vacuo to give 3.4 g and 97% yield of hydrobromide-2, -amino-5 (6) -hydroxymethylbenzimidazole.

The same product can also be obtained from 4-amino-3-nitrobenzyl alcohol without isolation of the diamine intermediate after hydrogenation. The filtrate obtained after removal of the hydrogenation catalyst is mixed with a solution of cyanogen bromide in methanol. The resulting product is then isolated as described above.

Example 11

250 mg of 1-dimethylaminosulfonyl-2-amino202556

The -5 (6) -hydroxymethylbenzimidazole is suspended in 7 ml of acetone and the mixture is cooled in an ice bath. 0.3 ml of Jones reagent is added to the cooled reaction mixture and the reaction is allowed to proceed for 5 minutes at 0 ° C. The mixture was poured into 40 ml of water. The aqueous mixture was extracted with chloroform (40 ml). The chloroform extracts are combined, washed with water and saturated sodium chloride solution and then dried. The chloroform was evaporated in vacuo to a solid residue which was recrystallized from ethyl acetate to give a first crop of 57 mg of 1-dimethylaminosulfonyl-2-amino-5 (6) -benzimidazole form.

For C 10 H 12 N 4 O 3 S (268) calculated: 44.71% C, H 4.51%, N 20.88%; Found: C, 44.75; H, 4.52; N, 20.63. Example 12

A) 4-Acetamidoacetone phenone

100 g of p-aminoacetophenone are added in portions to 400 ml of acetic anhydride. A small amount of pyridine is added to maintain a homogeneous solution. The reaction mixture was stirred at room temperature for 2 hours and then poured into 3.5 L of cold water. The precipitated product was collected to give 108.5 g (93% yield) of 5-acetamidoacetophenone.

For C 10 H 11 NO 2 (177) calculated: 67.78% C, 6.26% H, 7.90% N; found: 68.03 O / o C, 6.47% H, 8.02 θ / ο N.

B) 3-Nitro-4-acetamidoacetophenone 4 g of 4-acetamidoacetophenone was added portionwise to 25 ml of red fuming nitric acid at 0-5 ° C. After the addition was complete, the mixture was stirred for 15 minutes, then carefully poured into ice and the precipitated product was collected to give 3-nitro-4-acetamidoacetophenone in a yield of 4.7 g.

C) 3-Nitro-4-aminoacetophenone g of 3-nitro-4-acetamidoacetophenone in 160 milliliters of concentrated sulfuric acid was stirred at room temperature for 1 hour. The mixture was then carefully poured into cold water and the precipitated product was filtered off to give 3-nitro-4-aminoacetophenone (9.5 g, 73% yield).

For C 8 H 8 N 2 O 3 (180) calculated: 53.33% C, 4.48% H, 15.55% N; Found:% C, 53.18;% H, 4.33;% N, 15.87.

D) 2-Amino-5 (6) -acetylbenzimidazole

4.5 g of 3-nitro-4-aminoacetophenone were hydrogenated at 145 psi in 145 ml of ethyl acetate using 1 g of platinum oxide and 3 g of Raney nickel at room temperature. 3 equivalents of hydrogen are absorbed over 5 hours. The catalyst was removed by filtration, and 3 g of cyanogen bromide was added to the filtrate, followed by stirring for 24 hours. The product hydrobromide precipitated and was collected to give 2 g of 2-amino-5 (6) -acetylbenzimidazole hydride in amide.

For C 9 H 9 N 3 O.HBr (256) calculated: 42.21% C, 3.94% H, 16.41% N; Found:% C, 42.43;% H, 4.09;% N, 16.35.

E) 1-Dimethylaminosulfonyl-2-amino-5 (6) -acetylbenzimidazole (15.6 mmol) 2-amino-5 (6) -acetylbenzimidazole hydrobromide, 50 ml acetone, 5 milliliters (35.6 mmol) triethylamine and 2 3 g (16.0 mmol) of dimethylsulfamoyl chloride were heated at reflux for 12 hours. The mixture is filtered and the filtrate is evaporated in vacuo to a solid residue which is treated with 80 ml of methanol. The methanol solution is concentrated to 60 ml and cooled. The resulting product crystallized to give 800 mg of 1-dimethylaminosulfonyl-2-amino-5 (6) -acetylbenzimidazole as yellow crystals, m.p. 206 DEG-210 DEG C. with decomposition. For C 11 H 14 N 4 O 3 S (282) calculated: C 46.80, H 5.00, N 19.85; Found:% C, 47.07;% H, 4.99;% N, 65%. Example 13

A) The procedure of Example 19 was followed but starting from p-aminopropionfenone, 10 g (0.053 mol) of 2-amino-5 (6) -propionylbenzimidazole, 100 ml of acetone, 10 ml of triethylamine and 8.6 g of dimethylsulfamoyl chloride. The crude product was recrystallized from 600 mL of methanol to give 6.0 g of the 5-isomer, 1-dimethylaminosulfonyl-2-amino-5-propionylbenzimidazole, m.p. 206-208 ° C.

For C12H18N4O3S (296) calculated: 48.64% C, 5.44% H, 18.91% N; Found:% C, 48.41;% H, 4.49;% C, 18.73.

B) 2.8 g of the material insoluble in methanol are obtained from the solution remaining after the above crystallization, the material being 6-isomer, 1-dimethylaminosulfonyl-2-amino-6-propionylbenzimidazole, as confirmed by NMR spectrum.

For C12H18N4O3S (296) calculated: 48.64% C, 5.44% H, 18.91% N; Found: C, 48.58; H, 5.63; N, 18.71

The procedure of Example 12 was followed except that 5.7 g of 2-amino-5 (6) -butyrylbenzimidazole, 30 ml of acetone,

5.7 g of triethylamine, 4.0 g of dimethylsulfamoyl chloride to give 292 mg of 1-di-ethylaminosulfonyl-2-amino-5 (6) -butyrylbenzimidazole, m.p. 180.5-183 ° C.

For C 13 H 18 N 4 O 3 S (310) calculated: 50.31% C, 5.05% H, 18.05% N; Found: C 49.93, H 5.73, N 17.84. Example 15

A) 2-Amino-5 (6) -benzoylbenzimidazole ml (1.52 mol) of 4-aminobenzophenone was added portionwise with stirring to a solution of 250 ml of acetic anhydride in 250 ml of benzene. The temperature of the mixture rose to 70 ^° C. The reaction mixture was stirred overnight, the precipitated product was filtered, washed with benzene and dried. The yield of 4-acetamidobenzophenone was 333.8 g (91.5%), mp 150-152 ° C. A melting point of 155 ° C is reported in the literature (Chem. Abst. 55, 18 651).

g (0.1 mol of 4-acetamidobenzophenone, 50 ml of acetic anhydride and 20 ml of acetic acid are stirred and a solution of 15 ml of 90% nitric acid, 10 ml of acetic acid and 0.2 g of urea is added dropwise. The mixture is maintained at 50 DEG C. during the nitration, at the end of the nitration, the mixture is stirred at room temperature until it thickens, the thick slurry is then poured into ice, and the insoluble product is collected by filtration to remove

17.7 g and a yield of 62.5% yield 4-acetamido-3-nitrobenzophenone.

For C 15 H 20 O 4 (284.27) calculated: 63.38% C, 4.26% H, N 9.85%, O 22.51%;

Found:% C, 63.57;% H, 4.03;% N, 9.90.

g of 4-acetamido-3-nitrobenzophenone is added portionwise to 40 ml of sulfuric acid. The reaction temperature is adjusted with a water bath. The reaction mixture was stirred for 45 minutes and then poured into ice. The precipitated product is filtered to give 4-amino-3-nitrobenzophenone.

For C 13 H 10 N 2 D 3 (242.23) calculated: 64.46% C, 4.16% H, 11.56% N, 19.81% O;

Found:% C, 64.19;% H, 4.00;% N, 11.37.

g of 4-amino-3-nitrobenzophenone is hydrogenated at room temperature in 945 ml of tetrahydrofuran using 15 g of Raney nickel and at a pressure of 274 kPa. After 4 hours, 3 equivalents of hydrogen are absorbed. The catalyst was removed by filtration and the filtrate was evaporated in vacuo to a solid residue which was chromatographed on silica gel using ethyl acetate as eluent. Fractions 5-9 are combined to give 3,4-diaminobenzophenone in 43.6 g and 100% yield.

0.2 mol, 42.4 g of 3,4-diaminobenzophenone are dissolved in 100 ml of methanol and added to 1 liter of water. Cyanogen bromide (21.8 g, 0.2 mol) was added to the reaction mixture with stirring, and the mixture was stirred overnight, then filtered and the filtrate was neutralized to pH 7.0 with concentrated ammonium hydroxide. The precipitate was collected, washed with water and dried in vacuo to give an amount of 31 g and yield

68.5 a / _o yield 2-aminO'5 (6) -benzoylbenzimidazol.

For CWH11N3O (237.2) calculated: 70.87% C, 4.67% H, 17.71% N;

Found: C, 70.88; H, 4.60; N, 17.48.

B) 1-Dimethylaminosulfonyl-2-amino-5 (6) -benzoylbenzimidazole

4.5 g (20 mmol) of 2-amino-5 (6) -benzoylbenzimidazole are dissolved in 30 ml of acetone and 4.0 g of triethylamine. A solution of 2.9 g (20 mmol) of dimethylsulfamoyl chloride in 10 ml of acetone was added dropwise to the reaction mixture. The mixture was heated at reflux overnight, then poured into 400 water. The product was extracted with chloroform, the extract was washed with water, dehydrated with sodium sulfate and evaporated in vacuo to a solid residue which was crystallized from ethyl acetate to give 1.06 g of 1-dimethylaminosulfonyl-2-amino-6-benzoylbenzimidazole at a temperature mp 206-208 ° C.

For C 16 H 16 N 4 O 3 S (344) calculated: 55.82% C, 4.65% H, 16.28% N; Found: C, 56.27; H, 4.80; N, 15.95. Example 16 g (0.126 mol) of 2-amino-5- (6) -benzoyl-benzimidazole, 250 ml of dimethoxyethane and 6.3 g (0.13). mole of sodium hydride as a 50% suspension in mineral oil is stirred for 1 hour, then 19 g of isopro202536 pylsulfonyl chloride in 20 ml of dimethoxyethane are added and the mixture is stirred at room temperature for 16 hours, then heated at reflux for 2 hours. The mixture is cooled and concentrated in vacuo, dissolved in 1500 ml of ethyl acetate, washed with water, dehydrated and concentrated to 200 ml by boiling. After cooling the solution a precipitate is formed which is collected by filtration and washed with diethyl ether to give 11.1 g of 1- isopropylsulfonyl-2-amino-6-benzoylbenzimidazole, 6-isomer having a melting point of 185-186 [deg.] C. The later 5-isomer having a melting point of 142-143 [deg.] C.

Example 17

The procedure of Example 16 was repeated except starting from 1.1 g of 2-amino-5 (6) -p-chlorobenzoylbenzimidazole and 576 mg of dimethylsulfamoyl chloride to give 1-dimethylaminosulfonyl-2-amino-5 ( 6) -p-chlorobenzoylbenzimidazole. M / e 378.

Example 18

By the method of Example 15, 475 g of 2-amino-5 (6) -benzoylbenzimidazole, 2.5 moles of sodium hydride and 365 g of cyclohexylsulfonyl chloride were reacted to give 120 g of 1-cyclohexylsulfonyl-2-amino-6-benzoylbenzimidazole at a temperature mp 210-213 ° C with decomposition.

For C550H21N3O3S (383) calculated: 62.64% C, 5.52% H, 10.96% N; found: 62.43% S, 5.27% H, 10.51 O / o N. Example 19

According to the procedure of Example 15, 26.4 g (1.1 mol) of sodium hydride, 260 g (1.1 mol) of 2-amino-5 (6) -benzoylbenzimidazole and 200 g of thiophenylsulfonyl chloride are reacted to give 1 - ( thien-2-ylsulfonyl-2-amino-5- (6) -benzoyl-benzimidazole M / e 351.

The compounds of formula I have a broad spectrum of antiviral activity. They are particularly effective at inhibiting the growth of echo, Mengo, Coxsackie (A9,21, B5), poliovirus (type I, II,

III) or rhinoviruses (25 strains), but also inhibit various types of influenza viruses such as Ann Arbor, Maryland B, Massachusetts B, Hong Kong A, Pr-8a and Taylor C (types A, B). The ability of compounds of formula I to inhibit the growth of various viruses in vitro can be demonstrated using assays similar to those described in Siminoff, Applied Microbiology 9 (1), 66-72 (1961). Specific tests will be described in detail below.

Experimental methods

Monkey kidney cells (BSC-1) or Hela18

- Cells (5-3) are grown in 25 ml Falcon bottles at 37 ° C in medium 199 with 5% inactivated fetal bovine serum (FBS), with the addition of 150 units per ml penicillin and streptomycin in amounts 150 micrograms per ml. Once a single cell layer is formed, the culture medium is removed and 0.3 ml of the appropriate dilution of the selected virus (echo, Mengo, Coxsackie, poliovirus or rhlnovirus J) is added to each flask. After absorption for one hour at room temperature, infected the cell layer overlaps with an environment consisting of 1 part of 1% Ionagar No. 2 and 1 part of twice concentrated medium 199 with the addition of FBS, penicillin and streptomycin and containing 100, 50, 25, 12, 6, 3 and Stocks of thiazoline benzimidazole compounds or thiazinylbenzimidazole compounds of formula I were prepared in dimethyl sulfoxide at a concentration of 10 µg / ml, and the bottles were incubated for 72 hours at 37 ° C for poliovirus and ⁰ µg / ml. Coxsackie, echo, and Mengo viruses and rhinovirus for 120 hours at 32 ° C. Ann Arbor influenza virus, Maryland B Massachusetts B, Hong Kong A, Pr-8a and Taylor C (types A, B) were incubated at 37 ° C for 72 hours using MDCK cells (Madin-Darby dog kidney cells). Coatings were observed in areas where virus multiplication occurred in i cells. A solution of 10% formaldehyde and 2% sodium acetate was added to each flask to inactivate the virus and fix the cell layer to the surface of the substances. The plaques formed by the virus were counted regardless of their size after staining the surrounding areas with crystal violet. The number of coatings was compared with the number of coatings in the control bottle for each active agent concentration.

The efficacy of the test substance was expressed as a percentage reduction in plaque count. That is, the concentration of the active ingredient I50 denotes the concentration which inhibits the formation of speckled plaques to 50%. This concentration is a general measure of the effectiveness of the individual substances.

The results of the experiments are expressed by conversion to poliovirus type I, since this virus is easy to grow and reproducible results can be obtained. However, the efficacy of the compounds of formula I has also been demonstrated for other virus cultures, for example, Cpxackie viruses (A9, A21, B5J, echovirus (25 strains), poliovirus (type I, II, III) and influenza viruses such as Ann Arbor, Maryland B Massachusetts B, Hong Kong A, Pr-8a, and Taylor C (Type A, B).

The results for the various benzimidazole compounds of the formula I are summarized in Table I. The first column shows the example number, the second column the isomer type, columns 3 to 10 show the plaque reduction at different drug dilutions between 0.75 and 100 (Ug / ml.

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The 1-thiazolinylbenzimidazole compounds were investigated in pure form as a mixture of isomers. Both isomers inhibit the growth of the virus; wherein the 6-isomer is usually more potent than the 6-isomer.

The compounds of formula I suppress the growth of a number of viruses when added to the environment in which the virus grows. They can therefore be used in aqueous solutions, preferably with the addition of a surfactant for the decontamination of surfaces in which poliovirus, Coxsackie virus, rhinovirus or influenza virus, including glass used in hospitals, are present, all other surfaces especially used for the preparation food.

In addition, the compounds of the present invention may be administered orally to warm-blooded animals, including humans, at a dose of 1 to 300 mg / kg body weight. This may be repeated periodically if necessary. Usually, the active ingredient is applied every 4 to 6 hours.

The compounds of formula I are preferably used together with one or more excipients depending on the route of administration chosen. For oral administration, the compounds are mixed with non-toxic diluents or carriers such as lactose, sucrose, starch powder, cellulose, talc, magnesium stearate, magnesium oxide, calcium sulfate, acacia powder, gelatin, sodium alginate, sodium benzoate and stearic acid. . These dosage forms are formulated as tablets or capsules. In addition, the compounds of the invention may be administered parenterally.

The active compounds of the formula I can also be mixed with liquids and administered as nasal drops or intranasal sprays.

Claims (1)

přededmEt A process for the preparation of 1-sulfonylbenzimidazoles substituted on a carbonyl group of the general formula I (I) wherein R is alkyl of 1 to 4 carbon atoms, cycloalkyl of 5 to 7 carbon atoms, thienyl, or the group -NR 2 R 4 in which R 3 and R 4, the same or different, are alkyl of 1 to 3 carbon atoms, R 1 represents a hydrogen atom, R2 is hydrogen, C1-C4 alkyl, phenyl or halophenyl, Z represents an oxygen atom, a group Ynase is in the 5 or 6 position and n is 1, characterized in that a compound of formula II (f1) wherein R 2 and n are as defined above is reacted with a sulfonyl chloride of formula III RSO2CI (ΠΙ), where R is as defined above, in the presence of an organic solvent and optionally a base at room temperature to reflux.