GB1568543A

GB1568543A - 2-amino-or acylamino)-1-sulphonyl-benzoimidazole derivativves

Info

Publication number: GB1568543A
Application number: GB5254/77A
Authority: GB
Original assignee: Eli Lilly and Co
Current assignee: Eli Lilly and Co
Priority date: 1976-12-15
Filing date: 1977-02-09
Publication date: 1980-05-29
Also published as: IE44863B1; BG27742A3; SE8008090L; SU680645A3; AU509374B2; AU2244077A; CA1079737A; JPS6229429B2; ES456090A1; IE44863L; NL187396B; BE851630A; HU175361B; DK145645C; DE2706227A1; CS190339B2; MX4495E; FR2374311A2; IL51445A; PL196131A1

Abstract

Sulphonylbenzimidazole derivatives of formula <IMAGE> wherein R2 represents <IMAGE> and the substituents R, R5 and R6 are defined in Claim 1, are prepared by reacting a corresponding sulphonylbenzimidazole which instead of the substituent R2 has a group <IMAGE> with a C1-C7-alkyl-magnesium halide or C1-C7-alkyl-lithium and then performing a hydrolysis. Dehydration of the compounds of formula I gives compounds which contain the group <IMAGE> The compounds prepared may be used for the control of viruses.

Description

(54) 2-(AMINO OR ACYLAMINO)- 1-SULPHONYL- BENZIMIDAZOLE DERIVATIVES (71) We, ELI LILLY AND COM PANY, a corporation of the State of Indiana, United States of America, having a principal place of business at 307 East McCarty Street, City of Indianopolis, State of Indiana, United States of America, do hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement:- The incidence of viral upper respiratory disease is immense. It has been estimated that nearly a billion cases annually appear in the United States alone. Studies performed in England (Tyrrell and Bynoe, 1966) indicated that 74 percent of persons having colds were infected with rhinoviruses. Because more than 80 strains of rhinoviruses are already identified, the development of a practical rhinovirus vaccine is not feasible, and chemotherapy appears to be the more desirable approach.

The ability of chemical compounds to suppress the growth of viruses in vitro is readily demonstrated by using a virus plaque suppression test similar to that described by Siminoff, Applied Microbiology, 9(1), 66(1961).

Certain antifungal 1 - dimethylaminosulfonyl - 2 - aminobenzimidazole compounds have been disclosed in U.S. Patent Specification 3,853,908.

It is the purpose of this invention to provide novel benzimidazole compounds which inhibit the growth of viruses, particularly rhinoviruses, polio viruses, Coxsackie viruses, echo virus, and Mengo virus.

This invention concerns pharmacologically useful sulfonyl benzimidazole compounds having the general formula

wherein R is C1-C4 alkyl, C,-C, Cycloalkyl (as herein defined), thienyl, phenyl, or NRsR.t wherein R; and R4 are inde pendently C,-C, alkyl; R, is hydrogen, or C1-C4 acyl; R2 is

wherein R5 is C1-C4 alkyl, phenyl, halophenyl (as herein defined), or C3-C6 cycloalkyl (as herein defined); R6 is C1-C7 alkylidene; and R2 is at the 5 or 6 position.

The compounds of formula (I) are prepared by reacting a benzimidazole compound of the general formula

wherein R and R are defined as before, with a C,C alkyl magnesium halide or C,-C7 alkyl lithium, followed by hydrolvsis to form the compounds of formula (I) wherein R2 is

optionally followed bv dehydration to form the compounds of formula (I) wherein R2 is

and/or followed by acylation to obtain the compounds of formula (I) wherein R1 is C1-C4 acyl.

A preferred group of compounds are the compounds of formula (I) wherein R is C1-C4 alkyl or -NR3R4 wherein R3 and R4 are independently C1-C3 alkyl; and R1 is hydrogen.

An especially preferred group of compounds are the compounds of formula (I) wherein R is C1-C4 alkyl or -NR3R4 wherein R3 and R4 are independently C1-C3 alkyl; R1 is hydrogen; and R2is

wherein R5 is phenyl and R, is defined as before.

Illustrative of such preferred compounds are the following: 1 - dimethylaminosulfonyl - 2 - amino5(6) - (α - hydroxy - α - n - phenyllbenzyl)benzimidazole, 1 - dimethylaminosulfonyl - 2 - amino5(6) - [a - hydroxy - a(2,4 - dimethyl - 3pentyl )benzyl] benzimidazole, 1 - dimethylaminosulfonyl - 2 - amino5(6) - (a - hydroxy - e - n - hexylbenzyl)benzimidazole, 1 - dimethylaminosulfonyl - 2 - amino5(6) - (a - hydroxy - a - sec - butylbenzyl)benzimidazole, 1 -- dimethylaminosulfonyl - 2 - amino5(6) - (a - n propylidenebenzyl)benzimidazole, 1 - dimethylaminosulfonyl - 2 - amino5(6) - (a - n - pentylidenebenzyl)benzimidazole, 1 - dimethylaminosulfonyl - 2 - amino5(6) - (α - 2,4 - dimethyl - 3 - pentylidenebenzyl)benzimidazole, 1 - dimethylaminosulfonyl - 2 - amino 5(6) - (a - n - hexylidenebenzyl)benzimidazole, dimethylaminosulfonyl - 2 - amino 5(6) (a - sec - butylidenebenzyl)benzimidazole, 1 - isopropylsulfonyl - 2 - amino - 6 - aisopropylidenebenzylbenzimidazole, isopropylsulfonyl - 2 - amino - 5(6) - [α - hydroxy - α - (2,4 - dimethyl - 3- pentyl)benzyl]benzimidazole, and 1 - isopropylsulfonyl - 2 - amino - 5(6) (a - 2,4 - dimethyl - 3 - pentylidenebenzyl)benzimidazole.

Benzimidazole forms a tautomeric mixture in which either nitrogen atom has a hydrogen atom attached to it. The benzimidazole reactant bearing a substituent group at the 5 position of the benzene moiety therefore has a corresponding tautomeric form wherein the substituent resides alternatively at the 6 position. On replacing the hydrogen on the nitrogen atom with a substituent group, an isomer mixture is obtained. This is indicated herein by the designation 5(6) in the resulting compound.

The following definitions refer to the various terms used throughout this disclosure.

The term "C1-C4 alkyl" refers to methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secbutyl and tert-butyl. The term C1C, alkyl includes within its definition the term "C,- C3 alkyl". The term "C1C7 alkyl" refers to the straight and branched aliphatic radicals of one to seven carbon atoms including methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, isopentyl, hexyl, isohexyl, heptyl, isoheptyl, 2,4-dimethyl-3pentyl, t-butyl and neopentyl.

The terms "C3-C6 and C5-C7 cycoalkyl" refer to the optionally substituted saturated alicyclic rings of three to six and five to seven carbon atoms such as cyclopropyl, methylcyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1-, 2-, 3- or 4-methylcyclohexyl and cycloheptyl.

The term "halophenyl" refers to chlorophenyl or bromophenyl in which the single substituted atom is at any position of the phenyl ring.

The term "C1-C4,, refers to the straight and branched chain aliphatic acyl radicals of one to four carbon atoms such as formyl, acetyl, propionyl, butyryl, and 2-methylpropionyl.

The term "C1-C7 alkylidene" refers to straight and branched radicals of one to seven carbon atoms such as methylene, ethylidene, propylidene, isopropylidene, butylidene, isobutylidine, 3-methyl-2-butylidene, 2,4-dimethyl-3 -pentylidene, and n-hexylidene.

In the above process suitable dehydration agents are strong acids, such as p-toluenesulfonic acid, sulfuric acid, trifluoroacetic acid, methanesulfonic acid, or trifluoromethanesulfonic acid. The C1-C7 alkyl magnesium halide is an appropriate Grignard reagent. The C1-C7 alkyl lithium reagent results in a product in a similar fashion to the Grignard reagent. The preferred solvents for the alkylation process are inert organic solvents such as tetrahydrofuran, aromatics, such as benzene, or toluene; and ethers, such as diethyl ether. The preferred solvents for the dehydration process are aromatics, such as benzene or toluene; alkanes, such as hexane and halogenated hydrocarbons such as, methylene chloride and chloroform. The temperature range usually employed is from 25"C. to the reflux temperature of the solvent.

The starting materials of formula (II) are prepared as described in our pending application No. 35153/76 (Serial No. 1562812).

The product of the reaction is a l-sulfonylbenzimidazole compound. The product may be isolated by filtering the reaction mixture and concentrating 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 any insoluble material. The solution containing the sulfonylbeazimidazole compound is concentrated to crystallize the product or it is evaporated to give a second residue, which is dissolved in methanol for example. The sulfonylbenzimidazole compound is recovered from the methanol by crystallization.

The 5(6)-isomers are separable by fractional crystallization or by column chromato graph. Usually the 6-isomer crystallizes first from a a solution of the mixture.

The 2-acylamino sulfonylbenzimidazoles wherein R1 is other than hydrogen can be prepared preferably by acylating the corresponding 2-amino sulfonylbenzimidazole with the appropriate acid anhydrides. The isomeric 2-acetamido sulfonylbenzimidazoles can be separated by fractional crystallization from acetone, or preferably, methanol or ethanol.

The following examples further illustrate the preparation of the compounds of formula (I). The term "m/e" used in characterizing the products refers to the mass-to-charge ratio of ions which appear in the mass spectra of the products. In general, the values correspond to molecular weights of the major peaks.

Example 1.

To a solution of 600 ml. of tetrahydrofuran and 21.7 ml. (60 mmole) of methyl magnesium bromide in diethyl ether, under nitrogen, was added dropwise over 1 hour a solution of 4.1 g. (12 mmole) of 1 - dimethylaminosulfonyl - 2 - amino - 6 - benzoylbenzimidazole in 180 ml. of tetrahydrofuran. The mixture was refluxed for 5 hours, poured into ice and 1N hydrochloric acid, extracted twice with diethyl ether, washed with saturated sodium chloride, dried, and filtered to yield 2.9 g., as an amorphous solid, of 1 - dimethylaminosulfonyl - 2 - amino - 6 - (a - hydroxya - methylbenzyl)-benzimidazole. m/e 360.

Analysis: C1,H20N4O,S MW 360 Calcd: C, 56.67; H, 5.59; N, 1554 Found: C, 56.77; H, 5.46; N, 15.27 Example 2.

Two grams (5.5 mmole) of 1 - dimethylaminosulfonyl - 2 - amino - 6 - (a - hydroxya - methylbenzyl)benzimidazole in 130 ml. of chloroform was reacted with 1.3 g. of ptoluenesulfonic acid. The solution was refluxed with stirring for 6 hours. The solution was then washed with saturated sodium carbonate, dried, and filtered to yield 1.7 g. of 1 - dimethylaminosulfonyl - 2 -amino - 6 (a - methylenebenzyl)benzimidazole, m.p. 201 --2020C.

Analysis: Cl7Hl8N,02S MW 342 Calcd: C, 59.63; H, 5.30; N, 16.36 Found: C, 59.67; H, 5.35; N, 16.07 Example 3.

When the procedure of Example 1 was repeated using 100 ml. tetrahydrofuran, 22.2 ml. (60 mmole) of ethyl magnesium bromide (2.7 mmole/ml) in diethyl ether, and 4.1 g. of 1 - dimethylaminosulfonyl - 2 - amino - 6benzoylbenzimidazole, there was obtained 3.2 g., as a foam, of 1 - dimethylaminosulfonyl2 - amino - 6 - (a - ethyl - a - hydroxybenzyl) benzimidazole.

High resolution mass spec. for C18H22N4O,S Calcd: 374.14123 Found: 374.141 Example 4.

When the procedure of Example 2 was repeated using 1.2 g. (3.21 mmole) of 1dimethylaminosulfonyl - 2 - amino - 6 (aethyl a - hydroxybenzyl)benzimidazole, 750 mg. of p-toluenesulfonic acid, and 100 ml. of chloroform, there was obtained 388 mg. of 1dimethylaminosulfonyl - 2 - amino - 6 - (aethylidenebenzyl)benzimidazole, m.p. 200 202"C. (dec.).

High resolution mass spec. for C13H20N4O2S Calcd: 356.13107 Found: 356.131 Example 5.

When the procedure of Example 1 was repeated using 4.1 g (12 mmole) of 1 dimethylaminosulfonyl - 2 - amino - 6benzoylbenzimidazole in 180 ml. of tetrahydrofuran, 100 ml. tetrahydrofuran, and 28.6 ml. (60 mmole) of isopropyl magnesium chloride in 100 ml. of tetrahydrofuran, there was obtained, as a yellow foam, 4.0 g. of 1 - dimethylaminosulfonyl - 2 - amino - 6 (a - isopropyl - a - hydroxybenzyl)benzimidazole, yield 65%.

Example 6.

When the procedure of Example 2 was repeated using 1.2 g. (3.2 mmoles) of 1dimethylaminosulfonyl- 2 - amino - 6 - (aisopropyl - a - hydroxybenzyl ) benzimidazole, 750 mg. of p-toluenesulfonic acid, and 100 ml. of chloroform, there was obtained, as a beige solid, 82 mg. of 1 - dimethylamino sulfonyl - 2 - amino - 6 - ( < r - isopropylidene- benzyl )benzimidazole.

Example 7.

To a solution of 150 ml. of tetrahydrofuran and 31 ml. (84 mmole) of methyl magnesium bromide in diethyl ether, under nitrogen, was added dropwise a solution of 5.0 g. (15 mmole) of 1 - isopropylsulfonyl - 2 - amino6 - benzoylbenzimidazole in 200 ml. of tetrahydrofuran. The mixture was stirred at 250C. for 1 hour, reflexed for 2 hours, cooled, poured into ice and 1N hydrochloric acid, and extracted with diethyl ether. The 1500 ml. of solution was concentrated to 800 ml., dried, and concentrated under vacuum.

The product which formed was recrystallized from diethyl ether/hexane by dissolving the product in diethyl ether, adding diethyl ether/ hexane, and boiling the solution until turbid.

The solution was cooled to 25 C., refrigerated at 10"C., and filtered to yield 2 g. of product.

Additional product was recovered by concentration of the filtrate under vacuum, yield 2 g. The product was 1 - isopropylsulfonyl - 2amino - 6 - (a - hydroxy - a - methylbenzyl)benzimidazole. M/e 360, 344 base.

Analysis: C,,H,,N,OIS MW 359 Calcd: C, 60.15; H, 5.89; N, 11.69 Found: (first crop) C, 60.37; H, 5.73; N, 11.46 (second crop) C, 61.30; H, 6.26; N, 10.69 Example 8.

Two grams (5.6 mmole) of 1 - isopropylsulfonyl - 2 - amino - 6 - (a - hydroxy - a- methylbenzyl)benzimidazole in 100 ml. of chloroform was reacted with 1.3 g. of ptoluenesulfonic acid. The solution was refluxed with stirring for 4 hours. The solution was cooled to 250C. washed twice with saturated potassium carbonate, washed twice with water, dried over sodium sulfate, concentrated under vacuum, and recrystallized from diethyl ether/ hexane to yield 1.1 g., as light orange crystals, 1 - isopropylsulfonyl - 2 - amino - 6 - (amethylenebenzyl)benzimidazole, m.p. 1471480C. m/e 341.

Analysis: C,,H,.,N,OI SMW 341 Calcd: C, 63.32; H, 5.61; N, 12.31 Found: C, 63.58; H, 5.53; N, 12.15 Example 9.

When the procedure of Example 7 was repeated using 150 ml. of tetrahydrofuran, 31 ml. (84 mmole) of n-butyl magnesium bromide, 5.0 g. (15 mmole) of 1 - isopropylsulfonyl - 2 - amino - 6 - benzoylbenzimidazole, and reflexing for 20 hours, tliere was obtained 5.0 g., as a tan foam, of 1 - isopropylsulfonyl - 2 - amino - 6 - (a - hydroxy - n - butylbenzyl)benzimidazole.

Analysis: C23H,7N,O,S MW 401 Calcd: C, 62.82; H, 6.78; N, 10.47 Found: C, 63.14; H, 6.57; N, 10.17 Example 10.

When the procedure of Example 8 was repeated using 1 g. (2.5 mmole) of 1 - isopropylsulfonyl - 2 - amino - 6 - (a - hydroxya - n - butylbenzyl)benzimidazole, 75 ml. of chloroform, 600 mg. of p-toluenesulfonic acid, and refluxed for 90 minutes, there was obtained 790 mg. of 1 - isopropylsulfonyl2 - amino - 6 - (a - n - butylidenebenzyl)benzimidazole.

Analysis: C21H2,N3O2S MW 383 Calcd: C, 65.77; H, 6.57; N, 10.96 Found: C, 65.49; H, 6.31; N, 10.78 Example 11.

When the procedure of Example 7 was repeated using 40 ml. (85 mmole) of isopropyl magnesium bromide, 5.0 g. (15 mmole) of 1 - isopropylsulfonyl - 2 - amino 6- benzoylbenzimidazole and 200 ml. of tetrahydrofuran, there was obtained, as a yellow foam, 5.0 g. of 1 - isopropylsulfonyl - 2amino - 6 - (a - hydroxy a - isopropylbenzyl)benzimidazole. m/e 399.

Example 12.

When the procedure of Example 7 was repeated using 31 ml. (2.7 mmole in diethyl ether) of ethyl magnesium bromide, 5 g. (15 mmoles) of 1 - isopropylsulfonyl - 2 - amino6 - benzoylbenzimidazole, and 150 ml. of tetrahydrofuran, there was obtained, as a beige foam, 4.6 g. of 1 - isopropylsulfonyl2 - amino - 6 - (a - hydroxy - a - ethylbenzyl)benzimidazole. m/e 373, 343.

Example 13.

When the procedure of Example 8 was repeated using 890 mg. (2.4 mmole) of 1isopropylsulfonyl - 2 - amino - 6 - (ahydroxy - st - ethylbenzyl)benzimidazole, 50 ml. of chloroform, and 600 mg. of p-toluenesulfonic acid, there was obtained, as an amorphous foam, 630 mg. of 1 - isopropylsulfonyl2 - amino - 6 - (a - ethylidenebenzyl)benzimidazole.

Analysis: C,9H21N8O2S MW 355 Calcd: C, 64.20; H, 5.96; N, 11.82 Found: C, 63.93; H, 6.04; N, 11.64 Example 14.

When the procedure of Example 1 was repeated using 30 ml. (60 mmole) of npropyl magnesium bromide in 100 ml. of tetrahydrofuran, and 4.1 g. (5 mmole) of 1 - dimethylaminosulfonyl - 2 - amino - 6- benzoylbenzimidazole in 150 ml. of tetrahydrofuran, there was obtained, as a tan foam, 3.5 g. of 1 - dimethylaminosulfonyl 2 - amino - 6 - (a - hydroxy - a - n - propyl- benzyl)benzimidazole. m/e 388.

Example 15.

When the procedure of Example 1 was repeated using 80 ml. of tetrahydrofuran, 11.1 ml. of n-butyl magnesium bromide, and 2.05 g. of 1 - dimethylaminosalfonyl - 2amino - 6 - benzoylbenzimidazole in 90 ml. of tetrahydrofuran, there was obtained, as a white foam, 1.7 g. of 1 - dimethylaminosulfonyl - 2 - amino - 6 - (a - hydroxy - a- n - butylbenzylbenzimidazole. m/e 402.

Example 16.

When the procedure of Example 2 was repeated using 402 mg. of 1 - dimethylaminosulfonyl - 2 - amino - 6 - (a - hydroxy - an - butyl'benzyl)benzimidazole in 20 ml. of chloroform, 234 mg. of p-toluenesulfonic acid, and 100 ml. of chloroform, there was obtained 302 mg. of 1 - dimethylaminosulfonyl - 2amino - 6 - (a - n - butylidenebenzyl)benzimidazole. m/e 384.

The compounds of formula (I) exhibit a broad spectrum of antiviral activity. Not only are they especially effective in inhibiting the growth of echo virus, Mengo, Coxsackie, A9, 21,B5), polio (types I, II, III) or rhinovirus (25 strains) but they 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 compounds coming within the scope of formula (I) above to suppress the growth of different viruses in vitro is readily demonstrated by using a plaque suppression test similar to that described by Siminoff, Applied Microbiology, 9(1), 66-72 (1961). The specific tests are described in detail hereinbelow. The compounds of formula (I) were tested by the following methods.

Test Methods.

African green monkey kidney cells (BSC- 1) or Hela cells (5-3) were grown in 25 cc. Falcon flasks at 370C. in medium 199 with 5 percent inactivated fetal bovine serum (FBS), penicillin (150 units 1 ml.) and streptomycin (150 mcg./ml.). When confluent monolayers were formed, the supernatant growth medium was removed and 0.3 ml. of an appropriate dilution of virus (echo, Mengo, Coxsackie, polio or rhinovirus) was added to each flask. After absorption for one hour at room temperature, the virus infected cell sheet was overlaid with a medium comprising one part of 1 percent Ionagar No. 2 (Registered Trade Mark) and one part double strength medium 199 with FBS, penicillin, and streptomycin which contains drug at concentrations of 100, 50, 25, 12, 6, 3 and 0 micrograms per milliliter (mcg./ml.), The flask containing no drug served as the control for the test. The stock solutions of sulfonylbenzimidazole compounds were made up in dimethylsulfoxide dilution at a concentration of 104 mecg./ml. The flasks were incubated for 72 hours at 37"C. for polio, Coxsackie, echo, and Mango virus and 120 hours at 32"C. for rhinovirus. Plaques were seen in those areas where the virus infected and reproduced in the cells. A solution of 10 percent formalin and 2 percent sodium acetate was added to each flask to inactivate the virus and fix the cell sheet to the surface of the flask.

The virus plaques, irrespective of size, were counted after staining the surrounding cell areas with crystal violet. The plaque count was compared to the control count at each drug concentration. The activity of the test compound was expressed as percentage plaque reduction, or percent inhibition. Alternatively, the drug concentration which inhibits plaque formation by 50 percent can be used as a measure of activity. The 50 percent inhibition is indicated by the symbol 1.50.

Test results are expressed in terms of Polio virus type I inhibition because the virus is easy to grow and consistent test results are obtained. However, the activity of the compounds of formula (I) was confirmed against other virus cultures such as Coxsackie (A9, A21, B5), echo virus (strains 14, Mengo, rhinovirus (25 strains) and Polio (type I, II, III). Test results for various sulfonylbenzimidazole compounds are summarized in Table I below where column 1 give the Example number from the previous chemical examples, column 2 gives the isomer position of the corresponding benzimidazole product, and columns 3-10 indicate the percentage virus plaque reduction at drug dilutions from 0.75 -100 micrograms per milliliter (mcg/ml.).

TABLE I.

Plaque Reduction of 1-Substituted-sulfonyl-2-amino-5(6)-Substituted-Benzimidazoles

Drug Concentration (mcg/ml)* Example No. 100 50 25 12 6 3 1.5 0.75 1 6 ***mod. 100 100 96 62 45 0 0 toxic 2 6 toxic mod. sl.**** 100 100 100 100 51 toxic toxic 4 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 4 0 0 0 9 6 toxic toxic toxic 38 0 0 0 0 5 6 toxic mod. 78 40 33 0 0 0 toxic 8 6 toxic toxic toxic toxic 100 100 100 88 13 6 toxic toxic toxic toxic 100 100 100 100 10 6 toxic toxic toxic toxic 100 100 100 73 6 6 65 60 61 53 58 56 31 0 * Drug concentration in micrograms per milliliter ** Number 5 or 6 indicates respective isomer *** moderate toxicity observed **** slight toxicity observed The sulfonylbenzimidazole compounds of formula (I) were tested as pure compounds and as isomer mixtures. Both isomers inhibit virus growth, the 6-isomer generally being more active than the 5-isomer.

Compounds of formula (I) are able to suppress the growth of several viruses when added to a medium in which the virus is growing. The compounds of formula (I) can therefore be used in aqueous solution, preferably with a surfactant, to decontaminate surfaces on which polio, Coxsackie, rhinovirus or other viruses are present, such surfaces including hospital glassware and hospital working surfaces and similar areas in the preparation of food.

Furthermore, the compounds of formula (I) can be orally administered 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. In accordance with general practice, the antiviral compound can be administered every four to six hours.

Preferably, the compounds to be employed in accordance with the present invention are employed in combination with one or more adjuvants suited to the particular route of administration. Thus, in the case of oral administration, the compound is 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 compositions can be formulated as tablets or enclosed in capsules for convenient administration. In addition, the compounds can be administered parenterally.

The compounds can also be mixed with a liquid and administered as nose drops or intranasal spray.

Claims

WHAT WE CLAIM IS:

1. A sulfonyl benzimidazole compound of the general formula

wherein R is Cl-C4 alkyl, C5C, cycloalkyl (as herein defined), thienyl, phenyl, or NR,R4 wherein R, and R4 are inde pendently C18 alkyl; Rl is hydrogen, or C,-C4 acyl; R2 is

wherein - R5 is C1-C4 alkyl, phenyl, halophenyl (as herein defined), or C3Ce cycloalkyl (as herein defined; R6 is C1-C7 alkyl; R7 is C1-C7 alkylidene; and R2 is at the 5 or 6 position.

2. A compound of claim 1 wherein R is C1-C4 alkyl or -NR3R4 wherein R, and R4 are independently C1-C3 alkyl; and R1 is hydrogen.

3. A compound of claim 2 wherein R2 is

wherein R, is phenyl and R, is defined as in claim 1.

4. Any one of the following compounds of claim 1: 1 - dimethylaminosulfonyl - 2 - amino - 6 (a - hydroxy - a - methylbenzyl)benzimidazole, 1 - dimethylaminosulfonyl - 2 - amino - 6 (a - methylenebenzyl)benzimidazole, 1 - dimethylaminosulfonyl - 2 - amino - 6 (a - ethyl - a - hydroxybenzyl)benzimidazole, 1 - dimethylaminosulfonyl - 2 - amino - 6 (α - ethylidenebenzyl)-benzimidazole, 1 - dimethylaminosulfonyl - 2 - amino - 6 (a - isopropyl - a - hydrozybenzyl)benzimidazole, 1 - dimethylaminosulfonyl - 2 - amino - 6 (α - isopropylidenebenzyl)benzimidazole, 1 - isopropylsulfonyl - 2 - amino - 6 - (α- hydroxy - a - methylbenzyl)benzimidazole, 1 - isopropylsulfonyl - 2 - amino - 6 - (a- methylenebenzyl) benzimidazole, 1 - isopropylsulfonyl - 2 - amino - 6 - (ahydroxy - a - fl - butylbenzyl)benzimidazole, I - isopropylsulfonyl - 2 - amino - 6 - (an - butylidenebenzyl)benzimidazole, 1 - isopropylsulfonyl - 2 - amino - 6 - (α- hydroxy - α - isopropylbenzyl)benzimidazole, 1 - isopropylsulfonyl - 2 - amino - 6 (a - hydroxy - a - ethylbenzyl)benzimidazole, 1 - isopropylsulfonyl - 2 - amino - 6 - (a ethylidenebenzyl) benzimidazole, 1 - dimethylaminosulfonyl - 2 - amino - 6 (a - hydroxy - a - n - propylbenzyl)benzimidazole, 1 - dimethylaminosulfonyl - 2 - amino - 6- (a - hydroxy - a - fl - butylbenzyl)benzimidazole, 1 - dimethylaminosulfonyl - 2 - amino - 6 (a - n - butylidenebenzyl)benzimidazole.

5. A process for preparing the compounds of claim 1 which comprises reacting a compound of the general formula

wherein R and R, are defined as in claim 1, with a C1-C, alkyl magnesium halide or Cl-CT alkyl lithium, followed by hydrolysis to form the compounds of claim 1 wherein R2 is

optionally followed by dehydration to form the compounds of claim 1 wherein R2 is

and/or followed by acylation to obtain the compounds of claim 1 wherein R1 is C1-C4 acyl.

6. A compound as claimed in claim 1, substantially as hereinbefore described with particular reference to any one of the Examples.

7. A process as claimed in claim 5, substantially as hereinbefore described with particular reference to any one of the Examples.

8. A compound of formula (I) whenever prepared by a process according to claim 5 or 7.

9. A pharmaceutical formulation containing as active ingredient a compound of formula (I) as claimed in any one of claims 1 to 4, 6 or 8, associated with at least one pharmaceutically acceptable carrier therefor.