CH630368A5 - Process for the preparation of 1-sulphonyl-5(6)-subst.-benzimidazoles. - Google Patents

Description

The present invention has for its object to provide a method for producing new benzimidazole compounds which inhibit the growth of viruses, in particular rhinoviruses, polioviruses, coxsackieviruses, echoviruses and mengoviruses.

The invention relates to a process for the preparation of pharmacologically useful sulfonylbenzimidazole compounds of the general formula

\ /

in the

R represents Ci-C4-alkyl, Cs-C7-cycloalkyl, thienyl, phenyl or -NR3R4, in which R3 and R4 independently of one another denote Ci-C3-alk,

OH

I.

R2 represents Rs-C-, where Rs is Ci-C4-alkyl,

Ro

Phenyl, halophenyl or C3-C6 cycloalkyl means and

Rô is Ci-C7-alkyl, and

R2 is in the 5- or 6-position.

The process for the preparation of these compounds of the formula I is characterized in that a compound of the formula

■ NH

Y /

wherein

R and Rs have the definitions given above, reacted with a Ci-C7-alkyl magnesium halide or Ci-C7-alkyl-lithium and then hydrolyzed. Compounds of the formula s

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v /

, 0 - NH2 (I A)

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R

wherein

R is defined above and R2 'represents the group Rs-Cj-, where Rs above

R7

is defined and R? Ci-C7-alkylidene means

are obtained from compounds of the formula I by dehydration.

A preferred group of compounds are compounds of the formula (I) in which R represents Ci-C4-alkyl or -NR3R4, in which R3 and R4 independently of one another mean Ci-C3-alkyl.

A particularly preferred group of compounds are compounds of the formula (IA) in which R is Ci-C4-alkyl or -N R3R4, in which R3 and R4 independently of one another are Ci-C'j-alkyl and R2 'for Rs

't

R7

is where Rs is phenyl and R7 has the meaning given above.

Examples of such preferred compounds are the following:

l-dimethylaminosulfonyl-2-amino-5 (6) - (ct-hydroxy-a-n-pentylbenzyl (-benzimidazole,

l-dimethylaminosulfonyl-2-amino-5 (6) - [a-hydroxy-a- (2,4-dimethyl-3-pentyl) benzyl] benzimidazole, l-dimethylaminosulfonyl-2-amino-5 (6) - (a-hydroxy-an-hexylbenzyij-benzimidazole,

l-Dimethylaminosulfonyl-2-amino-5 (6) - (a-hydroxy-a-sec-butylbenzyl) benzimidazole, l-dimethylaminosulfonyl-2-amino-5 (6) - (an-propylidene-benzyl) benzimidazole ,

l-dimethylaminosulfonyl-2-amino-5 (6) - (a-n-pentylidene-benzyl) benzimidazole,

l-dimethylaminosulfonyl-2-amino-5 (6) - (a-2,4-dimethyl-3-pentylidenbenzyl) benzimidazole, l-dimethylaminosulfonyl-2-amino-5 (6) - (an-hexylidene-benzyl) - benzimidazole,

l-dimethylaminosulfonyl-2-amino-5 (6) - (a-sec-butylidene-benzyl (-benzimidazole,

l-isopropylsulfonyl-2-amino-6-a-isopropylidene-benzyl

benzirnidazole,

l-isopropyl sulfonyl-2-amino-5 (6) - [a-hydroxy-a- (2,4-dimethyl-3-pentyl) benzyl] benzimidazole and l-isopropyl sulfonyl-2-amino-5 (6 ) - (a-2,4-dimethyl-3-pentylidenebenzylj-benzimidazole.

The term “tautomeric benzimidazole” means a benzimidazole reagent that can be substituted with a hydrogen atom on each nitrogen atom. The benzimi-dazol reagent, which is unsubstituted on nitrogen and contains a substituent group in the 5-position of the benzene moiety, has a corresponding tautomeric form, in which the substituent is alternatively in the 6-position. The mixture of isomers can be designated as 5 (6) by numbering the corresponding positions.

The following definitions refer to the various statements and expressions used here. The

"Thienyl" means a thiophene group that is attached to the

2- or 3-position is bound.

The term “Ci-C4-alkyl” means straight-chain and branched-chain groups with 1 to 4 carbon atoms, namely methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl. The definition of “Ci-C4-alkyl” includes the definition of “Ci-C3-alkyl”. The term "Ci-C7-alkyl" means straight-chain and branched-chain groups with 1 to 7 carbon atoms, such as methyl, 10 ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, isopentyl, hexyl, isohexyl, heptyl , Isoheptyl, 2,4-dimethyl

3-pentyl, tert-butyl and neopentyl.

The term “C3-C7-cycloalkyl” means saturated rings with 3 to 7 carbon atoms, such as cyclopropyl, methylcy-15 clopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1-, 2-, 3- or 4-methylcyclohexyl and cycloheptyl.

The term “halophenyl” preferably means chlorophenyl or bromophenyl, monosubstituted at any point on the phenyl ring.

20 The term "Ci-C7-alkylidene" means straight-chain and branched-chain groups with 1 to 7 carbon atoms such as methylene, ethylidene, propylidene, isopropylidene, butylidene, isobutylidene, 3-methyl-2-butylidene, 2,4-dimethyl-3-penty -liden and n-hexylidene.

2s In the above process, suitable dehydrating agents are in particular strong acids such as p-toluenesulfonic acid, sulfuric acid, trifluoroacetic acid, methanesulfonic acid or trifluoromethanesulfonic acid. The C.i-C7-alkylmagnesium halide is a suitable Grignard reagent, whereby 30 is then hydrolyzed. The Ci-C7 alkyl lithium reagent gives a product that is similar to the Grignard reagent. The preferred solvents for these alkylation processes are inert organic solvents such as tetrahydrofuran; aromatic compounds such as benzene 35 or toluene; and ether such as diethyl ether. The preferred solvents for the dehydration process are aromatic compounds such as benzene or toluene; Alkanes such as hexane; and halogenated hydrocarbons such as methylene chloride and chloroform. The normally used temperature range is around 25 ° C up to the reflux temperature of the solvent.

The starting materials of formula (II) can be prepared as described in U.S. Patent Application 608,415 dated August 28, 1975. 45 The reaction product is a 1-sulfonylbenzimidazole compound. The product can be isolated by filtration of the reaction mixture and concentration of the filtrate to induce crystallization. Alternatively, the reaction mixture can be evaporated to dryness and the residue treated with a suitable solvent such as acetone or methanol to separate and remove insoluble material. The solution containing the sulfonylbenzimidazole compound is usually concentrated or evaporated to crystallize the product 55 to give a second residue which is dissolved, e.g. in methanol. The sulfonylbenzimidazole compound can be obtained from the methanol by crystallization.

The 5 (6) isomers are preferably separated by fractional crystallization or by column chromatography 60. The 6-isomer normally crystallizes out of the solution of the mixture first.

2-Acylaminosulfonylbenzimidazoles can preferably be prepared by N-acylation of a corresponding 2-aminosulfonylbenzimidazole obtained with suitable acid anhydrides 65. The isomeric 2-acetamidosulfonylbenzidimidazoles can be separated by fractional crystallization from acetone or, preferably, methanol or ethanol.

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The following examples illustrate the preparation of the compounds mentioned. The term “m / e” as used to characterize the products relates to the mass-to-charge ratio of the ions that occur in the mass spectrum of the products. In general, the values correspond to the molecular weights of the main peaks.

Exemplary embodiment 1 To a solution of 600 ml of tetrahydrofuran and 21.7 ml (60 mmol) of methyl magnesium bromide in diethyl ether, a solution of 4.1 g (12 mmol) of l-dimethylaminosulfonyl-2-amino- 6-benzoylbenzimidazole in 180 ml tetrahydrofuran. The mixture is heated under reflux for 5 h, poured onto ice and hydrochloric acid, extracted twice with diethyl ether, washed with saturated sodium chloride, dried and filtered; 2.9 g of amorphous solid of 1-dimethylaminosulfonyl-2-amino-6- (a-hydroxy-a-methylbenzyl) benzimidazole are obtained; m / e 360.

Analysis: C17H20N4O3S MW 360

Calc .: C 56.67% H 5.59% N 15.54%

Found: C 56.7% H 5.46% N 15.27%

Embodiment 2 2 g (5.5 mmol) of l-dimethylaminosulfonyl-2-amino-6- (a-hydroxy-cc-methylbenzyl) benzimidazole in 130 ml of chloroform are reacted with 1.3 g of p-toluenesulfonic acid. The solution is heated under reflux with stirring for 6 h. The solution is then washed with saturated sodium carbonate, dried and filtered; 1.7 g of 1-dimethylaminosulfonyl-2-amino-6- (a-methylenebenzyl) benzimide-azole are obtained, mp. 201 to 202 ° C.

Analysis: C17H18N4O2S MW 342

Calc .: C 59.63% H 5.30% N 16.36%

Found: C 59.67% H 5.35% N 16.07%

Embodiment 3 Use the procedure of Example 1 using 100 ml of tetrahydrofuran, 22 ml (60 mmol) of ethyl magnesium bromide (2.7 mmol / ml) in diethyl ether and 4.1 g of 1-dimethylaminosulfonyl-2-amino-6 -benzoylbenzimidazole repeated, 3.2 g of l-dimethylaminosulfonyl-2-amino-6- (a-ethyl-a-hydroxybenzyl) benzimidazole are obtained as a foam.

High resolution mass spectrum for C18H22N4O3S

Calculated: 374.14123 Found: 374.141

Exemplary Embodiment 4 The method of Example 2 is used using 1.2 g (3.21 mmol) of l-dimethylaminosulfonyl-2-amino-6- (cc-ethyl-a-hydroxybenzyl) benzimidazole, 750 mg of p-toluenesulfonic acid and 100 Repeating ml of chloroform, 388 mg of l-dimethylaminosulfonyl-2-amino-6- (a-ethylidene-benzyl) -benzimidazole, mp. 200 to 202 ° C (dec.).

High resolution mass spectrum for C18H20N4O2S

Calculated: 356.13107 Found: 356.131

4.1 g (12 mmol) of l-dimethylaminosulfonyl-2-amino-6-benzoylbenzimidazole in 180 ml of tetrahydrofuran, 100 ml of tetrahydrofuran and 28.6 ml (60 mmol) of isopropyl magnesium chloride are repeated in 100 ml of tetrahydrofuran to obtain 4. 0 g of l-dimethylaminosulfonyl-2-amino-6- (a-isopropyl-a-hydroxybenzyl) benzimidazole as a yellow foam; Yield 65%, m / e 388.

Analysis: C19H24N4O3S

Calc .: C 58.74% H 6.23% N 14.12%

Found: C 59.00% H 6.20% N 14.52%

Embodiment 6 If the method of Example 2 using

1.2 g (3.2 mmol) of l-dimethylaminosulfonyl-2-amino-6- (a-isopropyl-a-hydroxybenzyl) benzimidazole, 750 mg of p-toluenesulfonic acid and 100 ml of chloroform are repeated, giving 82 mg of l- Dimethylaminosulfonyl-2-amino-6- (a-isopropylidenbenzyl) benzimidazole as a beige solid.

Analysis: C19H22N4O2S

Calc .: C 61.60% H 5.99% N 15.12%

Found: C 61.38% H 5.81% N 14.85%

Embodiment 7 A solution of 5.0 g (15 mmol) of 1-isopropylsulfonyl-2-amino-6-benzoylbenzimidazole in 200 ml of tetrahydrofuran is added dropwise to a solution of 150 ml of tetrahydrofuran and 31 ml (84 mmol) of methyl magnesium bromide in diethyl ether under nitrogen . The mixture is stirred at 25 ° C. for 1 h, refluxed for 2 h, cooled, poured onto ice and in hydrochloric acid and extracted with diethyl ether. The 1500 ml solution is concentrated to 800 ml, dried and concentrated in vacuo. The product that forms is recrystallized from diethyl ether / hexane,

by dissolving the product in diethyl ether, adding diethyl ether / hexane and boiling the solution until it becomes cloudy. The solution is cooled to 25 ° C., stored in an ice cabinet at 10 ° C. and filtered; 2 g of product are obtained. Further product is obtained by concentrating the filtrate in vacuo; Yield 2 g. The product is 1-isopropylsulfonyl-2-amino-6- (a-hydroxy-a-methylbenzyl) benzimidazole; m / e 360,344 base.

Analysis: C18H21N3O3S MW 359

Calc .: C 60.15% H 5.89% N 11.69%

Found: (1st batch) C 60.37% H 5.73% N 11.46% (2nd batch) C 61.30% H 6.26% N 10.69%

Embodiment 8 2 g (5.6 mmol) of l-isopropylsulfonyl-2-amino-6- (a-hydroxy-a-methylbenzyl) benzimidazole in 100 ml of chloroform are reacted with 1.3 g of p-toluenesulfonic acid. The solution is heated under reflux with stirring for 4 h. The solution is cooled to 25 ° C., washed twice with saturated potassium carbonate and twice with water, dried over sodium sulfate, concentrated in vacuo and recrystallized from diethyl ether / hexane; 1.1 g of 1-iso-propylsulfonyl-2-amino-6- (a-methylenebenzyl) benzimidazole are obtained as light orange crystals, mp. 147 to 148 ° C .; m / e 341.

Analysis: C18H19N3O2S MW 341

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Embodiment 5 calculation: C 63.32% H 5.61% N 12.31%

Using the procedure of Example 1 using: C 63.58% H 5.53% N 12.15%

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Embodiment 9 Follow the procedure of Example 7 using 150 ml of tetrahydrofuran, 31 ml (84 mmol) of n-butylmagnesi umbromide, 5.0 g (15 mmol) of l-isopropylsulfonyl-2-amino-6-benzoyl-benzimidazole and 20 hours Repeated heating at reflux gives 5.0 g of l-isopropylsulfonyl-2-amino-6- (a-hydroxy-cc-n-butylbenzyl) benzimidazole as a dark yellow foam; m / e 401.

Analysis: C21H27N3O3S MW 401

Calc .: C 62.82% H 6.78% N 10.47%

Found: C 63.14% H 6.57% N 10.17%

Embodiment 10 Use the procedure of Example 8 using 1 g (2.5 mmol) of 1-isopropylsulfonyl-2-amino-6- (a-hydroxy-an-butylbenzyl) benzimidazole, 75 ml chloroform, 600 mg p-toluenesulfonic acid and refluxing for 90 minutes, 790 mg of 1-isopropylsulfonyl-2-amino-6- (an-butylidene-benzyl) -benzimidazole are obtained. m / e 383 (main peak), 276 [-S02CH (CH3) 2] UV (CH30H) ^ 2i2 e 35.166 7wo e 17.200

Analysis: C21H25N3O2S MW 383

Calc .: C 65.77% H 6.57% N 10.96%

Found: C 65.49% H 6.31% N 10.78%

Embodiment 11 If the procedure of Example 7 is repeated using 40 ml (85 mmol) of isopropyl magnesium bromide, 5.0 g (15 mmol) of 1-isopropylsulfonyl-2-amino-6-benzoylbenzimidazole and 200 ml of tetrahydrofuran, 5.0 is obtained g l-isopropylsulfonyl-2-amino-6- (a-hydroxy-a-isopropyl-benzyl) benzimidazole as a yellow foam; m / e 387. UV (CH3OH)? i2i3 e 39,300 cup e 16,800

Analysis: C20H25N3O3S MW 387

Calc .: C 61.99% H 6.50% N 10.84%

Found: C 61.74% H 6.25% N 10.64%

EXAMPLE OF EXAMPLE 12 If the procedure of Example 7 is repeated using 31 ml (2.7 mmol in diethyl ether) of ethyl magnesium bromide, 5 g (15 mmol) of l-isopropylsulfonyl-2-amino-6-benzoylbenzidimidazole and 150 ml of tetrahydrofuran, the result is obtained 4.6 g of l-isopropylsulfonyl-2-amino-6- (a-hydroxy-a-ethylbenzyl) benzimidazole as a beige foam; m / e 373.343.

UV (CHbOH) X213 e 33.528, read 14,000

Working Example 13 The procedure of Example 8 is repeated using 890 mg (2.4 mmol) of l-isopropylsulfonyl-2-amino-6- (a-hydroxy-a-ethylbenzyl-benzimidazole, 50 ml of chloroform and 600 mg of p-toluenesulfonic acid 630 mg of l-isopropylsulfonyl-2-amino-6- (a-ethylenedibenzyl) benzimidazole are obtained as an amorphous foam; m / e 355 (main tip),

248 (-S02CH) CHb) 2) UV (CH3OH)> .212 e 35,000, X.270 e 17,000

Analysis: C19H21N3O2S MW 355

Calc .: C 64.20% H 5.96% N 11.82%

Found: C 63.93% H 6.04% N 11.64%

EXAMPLE 14 The procedure of Example 1 is repeated using 30 ml (60 mmol) of n-propyl magnesium bromide in 100 ml of tetrahydrofuran and 4.1 g (5 mmol) of l-dimethylaminosulfonyl-2-amino-6-benzoylbenzimidazole in 150 ml of tetrahydrofuran. 3.5 g of l-dimethylaminosulfonyl-2-amino-6- (a-hydroxy- (xn-propylbenzyl) -benzimidazole are obtained as a dark yellow foam; m / e 388.

Analysis: C18H24N4O3S

Calc .: C 58.74% H 6.23% N 14.42%

Found: C 58.49% H 6.22% N 14.29%

Working Example 15 If the procedure of Example 1 is repeated using 80 ml of tetrahydrofuran, 11.1 ml of n-butylmagnesium bromide and 2.05 g of l-dimethylaminosulfonyl-2-amino-6-benzoylbenzimidazole in 90 ml of tetrahydrofuran, 1 is obtained , 7 g of l-dimethylaminosulfonyl-2-amino-6- (a-hydroxy-an-butylbenzyl) benzimidazole as a white foam; m / e 402.

Working Example 16 If the procedure of Example 2 is repeated using 402 mg of l-dimethylaminosulfonyl-2-amino-6- (cc-hydroxy-an-butylbenzyl) benzimidazole in 20 ml of chloroform, 234 mg of p-toluenesulfonic acid and 100 ml of chloroform, This gives 302 mg of l-dimethylaminosulfonyl-2-amino-6- (an-butylidenebenzyl) benzimidazole; m / e 384.

Working Example 17 According to the procedure of Example 8, but using 1.0 g of l-isopropylsulfonyl-2-amino-6- (a-hydroxy-a-isopropylbenzyl) benzimidazole, 75 ml of chloroform, 600 mg of p-toluenesulfonic acid Working under reflux conditions, l-isopropylsulfonyl-2-amino-6- (cc-isopropylidene benzyl) benzimidazole is obtained; m / e 369, UV (CH3OH) A / 213 8 34.700, X25S e 14.800, taso s 4.400.

EXAMPLE 18 According to the procedure of Example 8, but using 602 mg l-dimethylaminosulfonyl-2-amino-6- (a-hydroxy-an-propylbenzyl) benzimidazole, 20 ml chloroform, 362 mg p-toluenesulfonic acid, 93 mg are obtained 1-dimethylaminosulfonyl-2-amino-6- (an-propylidenbenzyl) benzimi-dazole.

Analysis: C19H24N4O2S

Calc .: C 61.60% H 5.99% N 15.12%

Found: C 61.53% H 6.14% N 15.01%

EXAMPLE 19 A solution of 5 g (13.1 mmol) of 1-cyclohexylsulfonyl-2-amino-6-benzyolbenzimidazole in 200 ml of tetrahydrofuran (under nitrogen) was quickly added dropwise to 84 ml of ethyl lithium. The reaction was carried out in an ice bath. After the reaction was complete, the solution was allowed to warm to a temperature of 25 ° without removing the ice bath and was left at that temperature for 2Vi hours. The reaction mixture was then stirred for 5 hours, diluted with water and the tetrahydrofuran was distilled off under vacuum. Then the product was extracted twice with chloroform, washed with a saturated sodium chloride solution, over sodium sulfate

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dried and filtered, and 4.1 g of 1-cyclohexylsulfonyl-2-amino-6- (a-ethylbenzyl) benzimidazole were obtained.

Analysis: C22H26N3O3S

Calc .: C 63.90% H 6.58% N 10.16%

Found: C 64.77% H 7.09% N 9.38%

Working Example 20 2 g of p-toluenesulfonic acid were added to a solution of 3.6 g (8.74 mmol) of 1-cyclohexylsulfonyl-2-amino-6- (a-hydroxy-a-ethylbenzyl) benzimidazole in 125 ml of chloroform . The reaction mixture was refluxed for 6 hours, cooled and then allowed to stand at ambient temperature for 12 hours. The product formed was washed with saturated sodium carbonate solution, dried over sodium sulfate, filtered and dried, yielding 5.25 g, in the form of a foam, of 1-cyclohexylsulfonyl-2-amino-6- (cc-ethylidenebenzyl) benzimidazole.

Analysis: C22H24N3O2S

Calc .: C 66.81% H 6.37% N 10.62%

Found: C 66.58% H 6.46% N 10.38%

Example 21 Following the procedure of Example 1, but using 500 ml of tetrahydrofuran, 60 ml of methyl magnesium bromide and 11.3 g of l-phenylsulfonyl-2-amino-6-benzoylbenzimidazole, 10 g of l-phenylsulfonyl-2-amino were obtained -6- (a-methyl-a-hydroxybenzyl) benzimidazole; m / e 373,365,234 (base), 165 and 104.

Analysis: C21H19N3O3S MW 393

Calc .: C 64.11% H 4.87% N 10.68%

Found: C 64.68% H 5.17% N 8.52%

Working Example 22 According to the procedure of Example 8, but using 2.7 g of l-phenylsulfonyl-2-amino-6- (a-hydroxy-a-methylbenzyl) benzimidazole, 250 ml of chloroform, 1.7 g of p-toluenesulfonic acid, working under reflux conditions for two hours gave 1.14 g of 1-phenylsulfonyl-2-amino-6- (a-methylenebenzyl) benzimidazole; F.P. 181-184 ° C, m / e 375.234 (base), 192.165 and 103.

Analysis: C21H17N3O2S MW375

Calc .: C 67 ,! 8% H 4.56% N 11.19%

Found: C 66.77% H 4.63% N 10.99%

Working Example 23 Following the procedure of Example 1, but using 473 ml of tetrahydrofuran, 0.3 mol of ethylmagnesi-umbromidine diethyl ether and 0.15 mol of 1-phenylsulfonyl-2-amino-6-benzoylbenzimidazole, 2.8 g were obtained in Form of a foam of l-phenyisulfonyl-2-amino-6- (a ~ ethyl-a-hydroxybenzyl) benzimidazole; m / e 389,378,248 (base), 105.

Analysis: C22H21N3O3S MW 407

Calc .: C 64.85% H 5.19% N 10.31%

Found: C 63.09% H 5.19% N 9.14%

Working Example 24 According to the procedure of Example 8, but using 2.9 g of l-phenylsulfonyl-2-amino-6- (cc-ethyl-a-

hydroxybenzyl) benzimidazole, 200 ml chloroform, 1.7 g p-toluenesulfonic acid, working under reflux conditions for 2 hours, 1 g of 1-phenylsul-fonyl-2-amino-6- (a-ethylidenbenzyl) benzimidazole, F.P. 152-153 ° C; m / e 389 (base), 300,248,233,165,115.

Analysis: C22H19N3O2S MW 389

Calc .: C 67.85% H 4.92% N 10.79%

Found: C 67.61% H 5.01% N 10.63%

Working Example 25 Following the procedure of Example 1, but using 500 ml of tetrahydrofuran, 60 ml of methyl magnesium bromide, 11.5 g of l-thienylsulfonyl-2-amino-6-benzoylbenzidimidazole, working under reflux conditions for 16 hours, was obtained l-thienylsulfonyl-2-amino (a-hydroxy-a-methylbenzyl) benzimidazole; m / e 399, 384,234,210,133,105 (base).

Analysis: C19H17N3O3S2 MW 399

Calc .: C 57.12% H 4.29% N 10.52%

Found: C 56.94% H 4.58% N 10.24%

Working Example 26 According to the procedure of Example 8, but using 5.71 g of p-toluenesulfonic acid, 250 ml of chloroform and l-thienylsulfonyl-2-amino-6- (cc-hydroxy-a-methyl-benzyl) -benzimidazole, the total amount obtained according to Example 25, working under reflux conditions for 8 hours, gave l-thienylsulfonyl-2-amino-6- (a-methylenebenzyl) benzimidazole; m / e 381 (base), 234,192,165,115

Analysis: C19H15N3O2S2 MW381

Calc .: C 59.82% H 3.96% N 11.02%

Found: C 57.53% H 4.11% N 8.99%

Embodiment 27 Following the procedure of Example 1, but using 0.02 mol of 1- (2-thienylsulfonyl) -2-amino-6-benzoylbenzimidazole in 500 ml of tetrahydrofuran, 3 mol of ethyl magnesium bromide, operating under reflux conditions , was obtained l- (2-thienylsulfonyl) -2-amino-6- (a-ethyl-a-hydroxybenzyl) benzimidazole; F.P. 120 ° C; m / e 413, 395,384,248 (base), 105.

Analysis: C20H19N3O3S2 MW 413

Calc .: C 58.09% H 4.63% N 10.16%

Found: C 55.72% H 4.44% N 9.77%

Working Example 28 Following the procedure of Example 8, but using 5.03 g of l- (2-thienylsulfonyl) -2-amino-6- (a-ethyl-a-hydroxybenzyl) benzimidazole, 250 ml of chloroform, 2.4 g Toluenesulfonic acid, working under reflux conditions, gave 4.08 g of l- (2-thienylsulfonyl) -2-amino-6- (a-ethylidenbenzyl) benzimidazole; F.P. 176-179 ° C; m / e 395,306,248 (base), 233,115.

Analysis: C20H17N3O2S2 MW 395

Calc .: C 60.74% H 4.33% N 10.62%

Found: C 60.52% H 4.57% N 10.61%

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Embodiment 29

Following the procedure of Example 1, but using 15 g of l-cyclohexylsulfonyl-2-amino-6-benzoylbenzimidazole, 500 ml of tetrahydrofuran and 78.0 ml of methyl magnesium bromide, working under reflux conditions, l-cyclohexylsulfonyl-2 was obtained -amino-6- (a-hydroxy-a-methylbenzyl) benzimidazole; m / e 381.235 (base), 104.

Analysis: C21H25N3O3S MW 399

Calc .: C 63.13% H 6.31% N 10.52%

Found: C 62.28% H 4.99% N 8.09%

Embodiment 30

Following the procedure of Example 8, but using the total amount of the product of Example 29, namely 1-cyclohexylsulfonyl-2-amino-6- (a-hydroxy-a-methylbenzyl) benzimidazole, 250 ml of chloroform and 7.6 g of p- Toluenesulfonic acid, working under reflux conditions for two hours, gave 13.1 g of I-cyclohexylsulfonyl-2-amino-6- (a-methylenebenzyl) benzimidazole; F.P. 187-189 ° C; m / e 381.235 (base), 220.165.103.

Analysis: C21H23N3O2S MW 381

Calc .: C 66.12% H 6.08% N 11.01%

Found: C 66.08% H 6.25% N 10.89%

The compounds of the formula (I) are antiviral agents with fire band action. They not only inhibit the growth of echo, mengo, coxsackie (A9, A21, B5), polio (types I, II, III) or rhinoviruses (25 strains) in a special way, but also inhibit various types of influenza viruses including Influenza strains such as Ann Arbor, Maryland B, Massachusetts B, Hong Kong A, Pr-8a and Taylor C (types A, B). The ability of the compounds of formula (I) to suppress the growth of different viruses in vitro is easily demonstrated using a platelet suppression test such as that described by Siminoff in Applied Microbiology, 9 (1), 66-72 (1961) Test. The specific experiments are explained in more detail below. The compounds of formula (I) are tested according to the following procedures.

Examination methods

Kidney cells (BSC-1) or Heia cells (5-3) African green monkeys are grown at a temperature of 37 ° C in 25 cm3 Falcon flasks in medium 199, which contains 5% inactivated fetal bovine serum (FBS), penicillin (150 Units / ml) and streptomycin (150 iig / ml). As soon as coherent monolayers have formed, the supernatant growth medium is removed and 0.3 ml of an appropriate virus dilution (echo, Mengo, Coxsackie, polio or rhinovirus) is added to each flask. After absorption for 1 h at room temperature, the cell layer infected with the viruses is covered with a medium composed of part 1% lonagar No. 2 and part double medium 199 with FBS, penicillin and streptomycin, the active substance concentrations of 100, 50.25 , 12.6.3 and 0 µg / ml. The flask that contains no active ingredient serves as a control for the examinations. The stock solutions of the sulfonylbenzimidazole compounds are prepared in dimethyl sulfoxide dilution at a concentration of 104 μg / ml. The flasks are incubated for 72 hours at 37 ° C for polio, coxsackie, echo and menoviruses and for 120 hours at 32 ° C for rhinoviruses.

Platelets can be seen where the virus has infected the cells and reproduces. A solution of 10% formalin and 2% sodium acetate is added to each flask to inactivate the virus and to fix the cell layer on the surface of the flask. The virus platelets are counted regardless of their size after staining the surrounding cell areas with crystal violet. The platelet count is compared to the control count at each drug concentration. The activity of the test compounds is expressed as a percentage of platelet reduction or percent inhibition. Alternatively, the drug concentration that inhibits platelet formation by 50% can be used as a measure of the activity. The 50% inhibition is indicated by the symbol I50.

The results obtained in the above experiments are expressed in terms of the inhibition of type I poliovirus, since the virus is easy to grow and consistent test results are obtained. The activity of the compounds of formula (I) is, however, also against other virus cultures such as Coxsackie (A9, A21, B5), echo (strains 1-4), Mengo-Rhino (25 strains) and polioviruses (type I, II , III) confirmed. The test results for various sulfonyl-benzimidazole compounds are summarized in Table I below, where in column 1 the number of the example from the previous chemical examples; in column 2 the 5 (6) position of the corresponding benzimidazole product; and in columns 3 to 10 the percentages of virus platelet reduction with active ingredient dilutions from 0.75 to 100 (ig / ml are given.

The sulfonylbenzimidazole compounds obtained according to the invention are tested as pure compounds and as mixtures of isomers. Both isomers inhibit virus growth, the 6 isomer is generally more active than the 5 isomer.

These compounds can suppress the growth of various viruses when added to a medium in which the virus grows. The compounds mentioned can therefore be used as aqueous solutions, preferably with a surface-active agent, for the decontamination of surfaces on which polio, coxsackie, rhinoviruses or other viruses are present, e.g. Hospital glassware and hospital work surfaces and similar surfaces as used for the preparation of food.

The compounds produced according to the invention can also be administered orally to warm-blooded mammals, including humans, in doses of 1 to 300 mg / kg of mammalian body weight. The administration can be repeated periodically as needed. Generally, the antiviral compound is administered every 4 to 6 hours.

The compounds mentioned are preferably mixed together with one or more adjuvants which are suitable for the particular route of administration. When administered orally, the compounds can be modified with pharmaceutical 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. Such preparations can be formulated in the form of tablets or enclosed in capsules for the appropriate administration. The compounds can also be administered parenterally. The compounds can also be mixed with a liquid and administered in the form of nasal drops or as an intranasal spray.

5

10th

15

20th

25th

30th

35

40

45

50

55

60

65

9 630368

Table I

Polio I platelet reduction by l-subst.-sulfonyl-2-amino-5 (6) -subst.benzimidazole example isomer drug concentration (jig / ml)

No.

(**)

100

50

25th

12

6

3rd

1.5

0.75

1

6

moderately toxic

100

100

96

62

45

0

0

2nd

6

toxic moderately toxic somewhat toxic

100

100

100

100

51

4th

6

100

100

100

100

100

100

100

100

7

6

100

100

100

85

50

28

15

1

12

6

toxic toxic

69

41

4th

0

0

0

9

6

toxic toxic toxic

38

0

0

0

0

5

6

toxic moderately toxic

78

40

33

0

0

0

8th

6

toxic toxic toxic toxic

100

100

100

88

13

6

toxic toxic toxic toxic

100

100

100

100

10th

6

toxic toxic toxic toxic

100

100

100

73

6

6

65

60

61

51

58

56

31

0

22

6

98

89

74

62

56

35

17th

5

24th

6

toxic toxic toxic toxic toxic

100

90

61

26

6

100

100

100

99

86

33

4th

0

28

6

100

100

100

100

100

100

99

85

30th

6

toxic toxic toxic toxic

100

96

46

0

* * The number 5 or 6 means the corresponding isomer

B

Claims (20)

630368 PATENT CLAIMS 1. Process for the preparation of sulfonylbenzimidazole compounds of the formula: - NH in which R is Ci-C4-alkyl, C5-C7-cycloalkyl, thienyl, phenyl or -NR3R4, in which R3 and R.4 independently of one another Ci Is -C3 alkyl; R2 is Rs-C-, where Rs is Ci-C4-alkyl, phenyl, Ra halophenyl or C3-C6-cycloalkyl; and Re is C 1 -C 7 alkyl; and R2 is in the 5- or 6-position, characterized in that a compound of the formula ■ NH V / in which R and Rs have the definitions given above, with a Ci-C7-alkylmagnesium halide or Ci-C7-alkyl-lithium implemented and then hydrolyzed. 1-dimethylaminosulfonyl-2-amino-6- (a ~ isopropylidene-benzyl) benzimidazole, characterized in that 1-dimethylaminosulfonyl prepared according to claim 1 1-dimethylaminosulfonyl-2-amino-6- (a-isopropylidene-benzyl) benzimidazole, characterized in that 1-dimethylaminosulfonyl prepared according to claim 1 2-amino-6- (a-isopropyl-a-hydroxybenzyl) benzimidazole is reacted with p-toluenesulfonic acid. 2-amino-6- (a-ethyl-a-hydroxybenzyl) benzimidazole is reacted with p-toluenesulfonic acid. 2nd 2nd v / in the R represents Ci-C4-alkyl, C5-C7-cycloalkyl, thienyl, phenyl or -NR3R4, in which R3 and R4 independently of one another mean Ci-C3-alkyl; R2 'represents Rs-C-, in which Rs Ci-C4-alkyl, phenyl, R7 Is halophenyl or C3-C6 cycloalkyl; and R7 is Ci-C7 alkylidene; and R2 'is in the 5- or 6-position, characterized in that compounds of the formula a— v / 2. The method according to claim 1, characterized in that R is Ci-C4-alkyl or-NR3R4, wherein R3 and R4 independently of one another Ci-C3-alkyl. 3rd 630368 wherein OH! R.2 stands for Rs-C-, in which Rs is defined above R « and Ró means Ci-C7-alkyl, produces and then dehydrated. 3. The method according to Anpsruch 1 for the preparation of l-dimethylaminosulfonyl-2-amino-6- (a-hydroxy-a-methyl-benzyl) -benzimidazole, characterized in that l-dimethylaminosulfonyl-2-amino-6-benzoylbenzimidazole with Reacts methylmagnesium bromide and then hydrolyzed. 4. The method according to claim 1 for the preparation of l-dimethylaminosulfonyl-2-amino-6- (a-ethyl-a-hydroxy-benzyl) benzimidazole, characterized in that l-dimethylaminosulfonyl-2-amino-6-benzoylbenzimidazole with Ethylmagnesiumbromid reacted and then hydrolyzed. 5 5. The method according to claim 1 for the preparation of l-dimethylaminosulfonyl-2-amino-6- (a-isopropyl-a-hydro-xybenzyl) -benzimidazole, characterized in that l-dimethylaminosulfonyl-2-amino-6-benzoylbenzimidazole with Isopropylmagnesiumchlorid reacted and then hydrolyzed. 6. The method according to claim 1 for the preparation of 1-iso-propylsulfonyl-2-amino-6- (a-hydroxy-a-methylbenzyl) -ben- zimidazole, characterized in that 1-isopropyl-sulfonyl-2-amino-6-benzoylbenzimidazole is reacted with methylmagnesium bromide and then hydrolyzed. 7. The method according to claim 1 for the preparation of 1-iso-propylsulfonyl-2-amino-6- (a-hydroxy-an-butylbenzyl) benzimidazole, characterized in that 1-isopropylsulfonyl-2-amino-6- reacted benzoylbenzimidazole with n-butyl-magnesium bromide and then hydrolyzed. 8. The method according to claim 1 for the preparation of 1-iso-propylsulfonyl-2-amino-6- (a-hydroxy-a-isopropylbenzyl) -benzimidazole, characterized in that 1-isopropylsulfonyl-2-amino-6- reacted benzoylbenzimidazole with isopropyl magnesium bromide and then hydrolyzed. 9. The method according to claim 1 for the preparation of 1-iso-propylsulfonyl-2-amino-6- (a-hydroxy-a-ethylbenzyl) -benzzi-midazole, characterized in that 1-isopropylsul-fonyl-2-amino- 6-benzoylbenzimidazole reacted with ethyl magnesium bromide and then hydrolyzed. 10th 10. The method according to claim 1 for the preparation of l-dimethylaminosulfonyl-2-amino-6- (a-hydroxy-an-propylbenzyl) -benzimidazole, characterized in that l-dimethylaminosulfonyl-2-amino-6-benzoylbenzimidazole with Reacts n-propyl magnesium bromide and then hydrolyzed. 11. The method according to claim 1 for the preparation of l-dimethylaminosulfonyl-2-amino-6- (a-hydroxy-an-butyl-benzyl) benzimidazole, characterized in that l-dimethylaminosulfonyl-2-amino-6-benzoylbenzimidazole with reacted n-butyl magnesium bromide and then hydrolyzed. 12. Process for the preparation of sulfonylbenzimidazole compounds of the formula R ' 13. The method according to claim 12, characterized in that R'2 for Rs-C- I. R? is where Rs is phenyl and R7 has the meaning given in claim 12. 14. The method according to claim 12 for the preparation of l-dimethylaminosulfonyl-2-amino-6- (a-methylenbenzyl) benzimidazole, characterized in that l-dimethylaminosulfonyl-2-amino-6- (a-hydroxy) prepared according to claim 1 -a-methylbenzyl) -benzimidazole with p-toluenesulfonic acid. 15. The method according to claim 12 for the production of 15 20th 25th 30th 35 40 45 50 55 60 65 16. The method according to claim 12 for the production of 17. The method according to claim 12 for the preparation of l-isopropylsulfonyl-2-amino-6- (a-methylenebenzyl) benzimidazole, characterized in that l-isopropylsulfonyl-2-amino-6- (a -hydroxy-a-methylbenzyl) -benzimidazole with p-toluenesulfonic acid. 18. The method according to claim 12 for the preparation of l-isopropylsulfonyl-2-amino-6- (an-butylidenbenzyl) benzimidazole, characterized in that l-isopropylsulfonyl-2-amino-6- (ct -hydroxy-an-butylbenzyl) -benzimidazole with p-toluenesulfonic acid. 19. The method according to claim 12 for the preparation of l-dimethylaminosulfonyl-2-amino-6- (an-butylidenbenzyl) benzimidazole, characterized in that prepared according to claim 1 dimethylaminosulfonyl-2-amino-6- (a-hydroxy-an -butylbenzyl) -benzimidazole with p-toluenesulfonic acid. 20. The method according to claim 12 for the preparation of l-isopropylsulfonyl-2-amino-6- (a-ethylidenbenzyl) benzimidazole, characterized in that l-isopropylsulfonyl-2-amino-6- (a -hydroxy-a-äthyibenzyl) -benzimidazole with p-toluenesulfonic acid. The upper respiratory tract is very often infected by viruses. In the United States alone, it is estimated that nearly 1 billion of such diseases occur each year. Corresponding studies carried out in England by Tyrell and Bynoe in 1966 show that 74% of people with colds are infected with rhinoviruses. Over 80 strains of rhinoviruses have been identified. The development of a simple rhinovirus vaccine is therefore not possible. The prospects for combating such diseases with chemotherapy drugs therefore appear to be more favorable. The ability of chemical compounds to suppress virus growth in vitro has already been demonstrated using a virus platelet suppression test similar to that described in Applied Microbiology, 9 (1), 66 (1961) by Siminoff. Certain antifungal 1-dimethylamino-sulfonyl-2-aminobenzimidazole compounds are described in U.S. Patent No. 3,853,908.