CA1079737A

CA1079737A - 1-sulfonyl-5(6)-substituted-benzimidazoles

Info

Publication number: CA1079737A
Application number: CA271,307A
Authority: CA
Inventors: Charles J. Paget; James W. Chamberlin; James H. Wikel
Original assignee: Eli Lilly and Co
Current assignee: Eli Lilly and Co
Priority date: 1976-12-15
Filing date: 1977-02-08
Publication date: 1980-06-17
Also published as: IE44863B1; JPS5377062A; BG27742A3; ZA77691B; AU509374B2; MX4495E; RO71886A; DK145645C; NL7701715A; PL196131A1; ATA111277A; GB1568543A; SE7701845L; PL106887B1; AT347937B; HU175361B; NL187396C; CS190339B2; IE44863L; BE851630A

Abstract

Abstract of the Disclosure Novel 1-sulfonyl-5(6)-substituted-benzimidazoles are described herein which are useful as antiviral agents.
The novel compounds are prepared by reacting the cor-responding 1-sulfonyl-5(6)-substituted-benzimidazole with a Gri?nard reagent or alkyl lithium, followed by hydrolysis, optionally followed by dehydration, and/or followed by acylation. The novel sulfonyl benzimidazole compounds have the general formula (I) , wherein R is C1-C4 alkyl, C5-C7 cycloalkyl, thienyl, phenyl, or -NR3R4 wherein R3 and R4 are independently C1-C3 alkyl;
R1 is hydrogen, or C1-C4 acyl;
R2 is or ;
wherein R5 is C1-C4 alkyl, phenyl, halophenyl, or C3-C6 cycloalkyl;
R6 is C1-C7 alkyl;
R7 is C1-C7 alkylidene; and R2 is at the 5 or 6 position.

Description

1~79'737 NOVEL l-SULFONYL-5(6)-SUBSTITUTED-BENZI~ ZOLES
The incidence of viral upper respiratory disease is immense. It has been estimated that nearly a billion cases annually appear in the United States alonea Studies performed in England (Tyrell 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, tne 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 growt~ of viruses in vitro is readily demonstrated by using a virus plaque suppression test s:im.ilar to that described by SiminoEE, Applied Microbiology, 9~1), 66~1961).
Certain antiungal 1-dimethylaminosulfonyl-2--aminobenzimidazole compounds have been disclosed in U. S.
Patent 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 sulEonyl benzimidazole compounds having the general formula R~ HR (I) ." ~

_ .. __ ..... . .. . ... .. , . . . . . . .. _ ~079737 :.
wherein ' R is Cl-C~ alkyl, C5-C7 cycloalkyl, thienyl, phenyl, ~:
or -NR3R~ wherein R3 and R4 are independently Cl-C3 ~lkyl;
Rl is hydrogen, or Cl-C4 acyl;

OH

R2 is 5 , or R5-C~

wherein R5 is CI-C~ alkyl, phenyl, halophenyl, or ;~
C3-C6 cycloalkyl;
R6 is Cl-C7 alkyl; ~:
R7 is C1-C7 alkylidene; and R2 is at the 5 or 6 position.
Th~ compounds o ormula (I) are prepared by reacting a tautomeric benæimidazole compound of the general formula ,:

RG--~C~~~ N~I2 (II) ~.
wherein R and R5 are deined as before, with a C1-C7 alkyl magnesium halide or Cl-C7 alkyl lithium, followed by hydrolysis to form the compounds of formula (I) wherei~ ~ ;
OH
R2 is R5-C- , optionally followed by dehydration to form R6 ', the compounds of formula (I) wherein R2 is R5-C- , and/or 7 :

., , ~ .

.. . , . , . ~

1~7g73'7 ~ollowed by acylation to ohtain the cornpounds of formula (I) wherein Rl i5 Cl-C4 acyl-~ preferred group of compounds are the compoundsof formula (I) wherein R iS Cl-C4 alkyl or -NR3R4 wherein R3 and R4 are independently Cl-C3 a:Lkyl; and Rl is hydrogen.
An especially preferred group of compounds are the compounds of formula (I) wherein R iS Cl-C4 alkyl or -NR3R4 wherein R3 and R4 are independently Cl-C3 alkyl;
Rl is hydrogen; and R is R -C-where:in R5 is phenyl ~nd R7 .is defined ~s be.Eore.
Illustrative of such preferred compounds are the ..
following:
l-dimethylaminosulfonyl-2-amino-5(6)-(-hydroxy--n-pentylbenzyl)benzimidazole, l-dimethylaminosulfonyl-2-amino-5(6)-[a-hydroxy--(2,4 -dimethyl-3-pentyl)benzyl]benzimidazole, l-dimethylaminosulfonyl-2-amino-5(6)-(a-hydroxy--n-hexylbenzyl)benzimidazole, l-dimethylaminosulfonyl-2-amino-5(6)-(a-hydroxy-a-se~=butylbenzyl)benzimidazole, l-dimethylaminosulfonyl-2-amino-5(6)-(a-n-propyl-idenebenzyl)benzimidazole, ~" :

l-dimethylaminosulfonyl-2-amino-5(6)~ n-pentyl-idenebenzyl)benzimidazole, l-dimethylaminosulEonyl-2-amino-5(6)-(~-2,4-dimethyl-3-pentylidenebenzyl)benzimidazole, l-dimethylaminosulfonyl-2-amino-5(6)-(a-n-hexyl-idenebenzyl)~enzimidazole, l-dimethylaminosulfonyl-2-amino-5(6)-~a-_ec-butylidenebenzyl)benzimidazole, l-isopropylsulfonyl-2-amino-6-a-isopropylidene-benzylbenzimidazole, l-isopropylsulfonyl-2-amino-5(6)-[a-hydroxy-a-(2,~-dimethyl-3-pentyl)benzyl]benzimidazole, and l-isopropylsuleonyl-2-amino-5(6)-(a-2,~-dimethyl~
3 pentyliclenebenzyl)berlzlmidazole.
The terrn "tautomeric ben~imidazole" reEers to a benzimidazole reagent which can be substituted at either nitrogen atom with a hydrogen atom. The benzimidazole reactant, unsubstituted on nitrogen and bearing a substit-uent group at the 5 position of the benzene moiety, has a corresponding tautomeric form wherein the substituent resides alternatively at the 6 position. The isomer mixture can be indicated by numbering the alternate positions as 5(6).
The following definitions refer to the various terms used throughout this disclosure. The term "thienyl"
refers to the thiophene radical attached at the 2 or 3 position.

The terrn "Cl-C4 alkyl" refers to the straight and bran-hed aliphatic radicals o~ one to four carbon atoms inclllding methyl ethyl propyl isopropyl butyl isobutyl ~ .
sec-butyl and tert-butyl. The term Cl-C4 alkyl includes within its definition the terms "Cl-C3 alkyl" The term "Cl-C7 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-3-pentyl, t-butyl and neopenty}.
The term "Cl-C4 alkyl carbinol" refers to the stra.ight and branched aliphatic alcohols of one to four carbon atoms as exemplified in the term "Cl-C4 alkyl."
The term "C3-C7 cycloalkyl" re.Eers to the sat- ~ ;
urat(3d alicyclic r.ings of three to seven carbon at:om~ such as cyclopropyl, methylcyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1- 2- 3- or 4-methylcyclohexyl and cyclo-heptyl .
The term "halophenyl" refers to chlorophenyl or bxomophenyl mono-substituted at any position of the phenyl ring.
The term "Cl-C4 acyl" refers to the straight and branc~hed chain aliphatic acyl radicals of one to four carbon atoms such as formyl, acetyl propionyl butyryl and 2-methylpropionyl.
The term "Cl-C7 alkylidene" refers to straight ~ :
and branched radicals of one to seven carbon atoms such as methylene, ethylidene, propyl.idene, isopropylidene butyl-iden(_ isobutylidene, 3-methyl-2-butylidene 2,4-dimethyl-3-pentylidene, and n-hexylidene.

X-4571E . -6-.

~L~79~37 In the above process suitable dehydration agentsare strong acids, such as p-toluenesulfonic acid, sulfuric acid, trifluoroacetic acid, methanesulfonic acid, or tri-fluoromethanesulfonic acid. The Cl-C7 alkyl magnesium halide is an appropriate Grignard reagent followed by hydrolysis. The Cl-C7 alkyl lithium reagent results in a product similar 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 pre-ferred solvents for the dehydration process are aromatics, such as benzene or toluene; alkanes, such as hexane; and halocJenated hydrocarbons such as, methylene chloride and chloroform. The temperature range usually employed is from about 25C. to the reflux temperature of the solvent.
The starting materials of formula (II) are prepared as described in Canadian Patent No. 1,063,501, of Paget et al, granted October 16, 1979.
The product of the reaction is a l-sulfonylbenz-imidazole compound. The product may be isolated by filter-ing 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 sulfonylbenzimidazole compound is concentrated to crys-tallize 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 meth-anol by crystallization.

7~7 The 5(6)-isomers are separable by fractional crys-tallizatiGn or by column chromatography. Usual]y the 6-isomer crystallizes first from a solution of the mixture.
The 2-acylamino sulfonylbenzimidazoles wherein R
is ot:her than hydrogen can be prepared preferably by acyl-ating the corresponding 2-amino sulfonylbenzimidazole with the appropriate acid anhydrides. The isomeric 2-acetamido sulfc,nylbenzimidazoles 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-char~e ratlo of ions which appear in the mass spectra of the proflvcts. In g~neral, the values corre.sponcl to molecular weiyhts 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 l-dimethylaminosulfonyl-

2-amino-6-benzoylbenzimidazole in 180 ml. of tetrahydro-furan. The mixture was refluxed for 5 hours, poured into ice and lN 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-hydroxy-a-methylbenzyl)-benzimidazole. m/e 360.

~ ~.

:. , .~ ' " ,' . ' :

7~

Calcd: C, 56.67; ~1, 5.59; N, 15.54 Found: C, 56.77; H, 5.46; N, 15.27 Example 2 Two grams (5.5 mmole) of l-dimethylaminosulfonyl-2-amino-6-(a-hydroxy-a-methylbenzyl)benzimidazole in 130 ml.
of chloroform was reacted with 1.3 g. of p-toluenesulfonic 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 dimethylamino-sulfonyl-2-amino-6-(a-methylenebenzyl)benzimidazole, m.p.
201-;~02C.
Analy5is C17ll18N~2~ MW 342 Calccl: C, 59.63; Il, 5.30; N, 16.36 Found: C, 59.67; Il, 5.35; N, 16.07 Example 3 When the procedure of Example 1 was repeated usinc~ 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-6-benzoylbenzimida-zole, there was obtained 3.2 g., as a foam, of l-dimethyl-aminosulEonyl-2-amino-6-(a-ethyl-a-hydroxybenzyl)benzimi-dazole.
High resolution mass spec. Eor C18H22N4O3S
Calcd: 374.14123 Found: 374.141 X-4571E -g-~9737 ExampLe 4 When the procedure o~ Example 2 was repeated using 1.2 g. (3.21 mmole) of 1-dirnethylaminosulfonyl~2-amino-6-(a-ethyl-a-hydroxybenzyl)benzimidazole, 750 mg. of p-toLuenesulfonic acid, and 100 ml. of chloroform, there was obtained 388 mg. of 1-dimethylamlnosulfonyl-2-amino-6-(a-ethylidenebenzyl)benzimidazole, m.p. 200-202C. (dec.) High resolution mass spec. for C18H20N4O2S
Calcd: 356.13107 Found: 356.131 Example 5 When the procedure of Example 1 was repeated using 4.1 g. (12 mmole) of l-dlmethyLaminosul~onyl-2-amino~6-benzoylbenzLmidazole in 1~0 ml. o~ tetrahydroEuran, 100 ml. tetrahydrofuran, ancl 28.6 mL. (60 mrnole) of iso-propyl magnesium chloride in 100 ml. of te-trahydrofuran, there was obtained, as a yellow foam, 4.0 g. of l-dimethyl-aminosulfonyl-2-amino-6-(a-isopropyl-a-hydroxybenzyl)benz-imidazole, yield 65%.
Example 6 When the procedure of Example 2 was repeated using 1.2 g. (3.~ mmoles) of 1-dimethylaminosul~onyl-2-amino-6-(a-isopropyl-a-hydroxybenzyl)benzimidazole, 750 mg. of _-toluenesulfonic acid, and 100 ml. of chloroform, there was obtained, as a beige solid, 82 mg. of l-dimethylaminosul~
fonyl-2-amino-6-(a-isopropylidenebenzyl)benzimidazole.

. .

1~79-737 Example 7 To a solution of 150 ml. of tetrahydrofuran and 31 ml. (84 mmole) of methyl magnesium bromide in cliethyl ether, under nitrogen, was added dropwise a solution of 5.0 g. (15 mmole) of 1-isopropylsulfonyl-2-amino-6-benzoyl-benzimidazole in 200 ml. of tetrahydrofuran. The mixture -was stirred at 25C. for 1 hour, refluxed for 2 hours, cooled, poured in-to ice and lN 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 25C., re~ri~erated at 10C., and filtered to yield 2 ~3. of product. Additional product was recovered by concentration of the filtrate under vacuum, yield 2 g. The product was l-isopropylsulfonyl-2-amino-6-(a-hydroxy-a-methylbenzyl)benzimidazole. m/e 360, 344 base.
Ana y 18 21 3 3 Calcd: C, 60.15; H, 5.89; N, 11.69 Found (first crop) C, 60.37; ~I, 5.73; ~, 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 p-toluenesulfonic acid. The solution was refluxed with stirring for 4 hours.

The solution was cooled to 25C., washed twice with saturated potassium carbonate, washed twice with water, dried over sodi~m sulfate, concentrated under vacuum, and recrystal~
lized from diethyl ether/hexane to yield 1.1 g., as light orange crystals, l-isopropylsulfonyl-2-amino-6-(a-methylene-benzyl)benzimidazole, m.p. 147-148C. m/e 341.
naly is C18 1gN32 MW 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 lS0 ml. of tetrahydrofuran, 31 ml. (84 mmole) oE n-butyl magnesium bromide, 5.0 y. (L5 mmole) o~ J-i.sopropylsulfonyl-2-amir)o-6-benzoylbenzimidazole, ancl reeluxlng Eor 20 hours, there was obtained 5.0 y., as a tan Eoam, of 1-isopropyl-sulfonyl-2-amino-6-(a-hydroxy-a-n-butylbenzyl)benzimidazole.
Analysis C21H27N3O3S 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 y. (2.5 mmole) of 1-isopropylsulfonyl-2-amino-6-(a-hydroxy-a-n-butylbenzyl)benzimidazole, 75 ml. of chloroform, 600 mg.
of _-toluenesulfonic acid, and refluxed for 90 minutes, there was obtained 790 mg. of 1-isopropylsulfonyl-2-amino-6-(a-n-butylidenebenzyl)benzimidazole.
Analysis C21H25N32S MW 383 Calcd: C, 65.77; H, 6.S7; N, 10.96 Found: C, 65.49; H, 6.31; N, 10.78 X-457lE -12-1~7~737 ~xample ll When the procedure of Example 7 was repeated using 40 ml. (85 mmole) of isopropyl magnesium bromide, 5.0 g. (15 mmole) of l-isopropylsulfonyl~2-amino-6-benzoyl-benzimidazole and 200 ml. of tetrahydrofuran, there was obta.ned, as a yellow foam, 5.0 g. of l isopropylsulfonyl-2-amino-6-(a-hydroxy-a-isopropylbenzyl)benæimidazole.
m/e 399.

Example 12 When the procedure of E'xample 7 was repeated usin~l ~1 ml. (2.7 mmole in diethyl ether) Oe ethyl macJnesium bromide, 5 g. (15 mmoles) of L-isopropylsulonyl-2-amino-6-benzoylbenzimidazole, and 150 ml. of -tetrahydrofuran, there was obtained, as a beige foam, 4.6 g. of l-isopropylsulfonyl-2-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 l-lsopropylsulEonyl-2-amino-6-(c~-hydroxy-a-ethylbenzyl)benzimidazole, 50 ml. of chloro-form, and 600 mg. of p-tc~luenesulfonic acid, there was obta~ned, as an amorphous foam, 630 mg. of 1-isopropyl-sulfonyl-2-amino-6-(-ethylidenebenzyl)benzimidazole.

.

: : -.

~l~79'737 :

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 n-propyl magnesium bromide in 100 ml.
of tetrahydrofuran, and 4.1 g. (5 mmole) of l-dimethylamino-sulfonyl-2-amino-6-benzoylbenzimidazole in 150 ml. of tetra-hydrofuran, there was obtained, as a tan foam, 3.5 g. of 10 1-dimethylaminosulfonyl-2-amino-6-(~-hydroxy-a-n-propyl-benzyl)benzimidazole. m/e 388.
Example 15 When the procec]ure o~ Example 1 was repeated using 80 ml. oE tetrahydrofuran, Ll.l ml. oE n-butyl ma~lne~ium bromicle, and 2.05 g. of 1-dimethylarninosulfonyl-2-amino-6-benzoylbenzimidazole in 90 ml. of tetrahydrofuran, there was obtained, as a white foam, 1.7 g. of l-dimethylaminosulfonyl-2-amino-6-(~-hydroxy-a-n-butylbenzyl)benzimidazole. m/e 402.

~xample 16 When the procedure of Example 2 was repeated using :
402 mg. of 1-dimethylaminosulfonyl-2-amino 6-(~-hydroxy-a-n-butylbenzyl)benzimidazole in 20 ml. of chloroform, 234 mg.
of p-toluenesulfonic acid, and 100 ml. of chloroform, there ~ ?
was obtained 302 mg. of 1-dimethylaminosul~onyl-2-amino-6-(a-n-butylidenebenzyl)benzimidazole. m/e 384.

, f ~C~79737 ~ he compounds of formula (I) exhibit a broad spec-trum of antiviral activity. Not only are they especially effective in inhibi~ing the growth of echo virus, Mengo, Coxsackie, (A9, A21,B5), polio (types I, II, III) or rhino-virus (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 ~pecific 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-l) or ~ela cells (5-3) were grown in 25 cc. Falcon flasks at 37C. 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. Af~er absorption for on~ hour at room temperature, the virus infected cell ~- sheet was overlaid with a medium comprising one part of 1 percent Ionagar No. 2 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 micro-:.

:
X-457lE -15-1~7~737 grams per milliliter (mcg./ml.). The flask containing no drug served as the control for the test. The stock solu-tions o~ sul~onylbenzimidazole compounds were made up in dimet:hylsulfoxide dilution at a concentration of 10~ mcg./ml.
The ilasks were incubated for 72 hours at 37C. for polio, Coxsackie, echo, and Mengo virus and 120 hours at 32C. for rhinovirus. Plaques were seen in those areas where the virus infected and reproduced in the cel.ls. A solution of ~:
10 percent formalin and 2 percent sodium acetate was added to each flask to inactivate the vi.rus and fix the cell sheet to the surface of the flask. The virus plaques, irrespective of size, were counted after staining the surrounding cell areaC with crystal violet. The plaque count was compared to the control count at each drug concentrAtion. The activity Oe the tcst compound was expre5sed as percentacJe 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 inhibi-tion is indicated by the symbol I50.
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 conEirmed against other virus cultures such as Coxsackie (A9, A21, BS), echo virus (strains 1-4), Mengo, rhinovirus (25 strainsl and Polio (type I, II, III). Test results for various sulfonylbenz-imidazole compounds are summarized in Table I below where column 1 give the Example number from the previous chemical X-~571E -16- !~

~L~7~737 -;sa~n:,lcs, column ~ ~JiVCS thc '; ~6) -position of the corre-spondiny benzimidazole product, and columns 3-10 indicate the percentage virus plaque reduction at drug dilutions from 0.75-100 micrograms per milliliter (mcg./ml.).

.

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~C379737 The sulfonylbenzlmidazole compounds of formula (I) were tested as pure compounds and as isomer mixtures. Both isomers inhibit virus growth, the 6-isomer generall~ 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 surEaces and similar areas in the preparation of food.
Furthermore, the compounds of formula (I) can be orally admlnistered to warm-blooded mammals includincJ hùmans .in doses of 1 to 300 m~./k~. Oe mammalian body weiyht. 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 par-ticular route of administration. Thus, in the case of oral administration, the compound is mod.iEied 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 compo-sitions can be formulated as tablets or enclosed in capsules for convenient administration. In addition, the compounds can be administered parenterally.

~979~37 : ~:
The compounds can also be mixed with a liquid and ~
administered as nose drops or intranasal spray. ~ :

j X-4571E -20- ~ , ' ~ "

!... . . . ~ . : . ~
,: ~ . ,, . ~

Claims

The embodiments of the invention in which an exclusive property or pxivilege is claimecl are defined as follows:

1. A process for preparing a sulfonyl benzimida-zole compound of the general formula (I) wherein R is C1-C4 alkyl, C5-C7 cycloalkyl, thienyl, phenyl, or -NR3R4 wherein R3 and R4 are independently C1-C3 alkyl;

R1 is hydrogen, or C1-C4 acyl;

R2 is or ;

wherein R5 is C1-C4 alkyl, phenyl, halophenyl, or C3-C6 cycloalkyl;

R6 is C1-C7 alkyl;

R7 is C1-C7 alkylidene; and R2 is at the 5 or 6 position, which comprises reacting a compound of the general formula (II) wherein R and R5 are defined as above, with a C1-C7 alkyl magnesium halide or C1-C7 alkyl lithium, followed by hy-drolysis to form the compounds of formula I wherein R2 is , optionally followed by 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.

2. A sulfonyl benzimidazole compound of the general formula (I) wherein R is C1-C4 alkyl, C5-C7 cycloalkyl, thienyl, phenyl, or -NR3R4 wherein R3 and R4 are independently C1-C3 alkyl;
R1 is hydrogen, or C1-C4 acyl;

R2 is or ;

wherein R5 is C1-C4 alkyl, phenyl, halophenyl, or C3-C6 cycloalkyl;

R6 is C1-C7 alkyl;
R7 is C1-C7 alkylidene; and R2 is at the 5 or 6 position, whenever prepared by the process of claim 1 or an obvious chemical equivalent.

3. A process of claim 1 wherein R is C1-C4 alkyl or -NR3R4 wherein R3 and R4 are independently C1-C3 alkyl; and R1 is hydrogen.

4. A compound of claim 2 wherein R is C1-C4 alkyl or -NR3R4 wherein R3 and R4 are independently C1-C3 alkyl; and R1 is hydrogen, whenever prepared by the process of claim 3 or an obvious chemical equivalent.

5. A process of claim 3 wherein R1 is hydrogen and R2 is wherein R5 is phenyl and R7 is C1-C7 alkyli-dene.

6. A compound of claim 2 wherein R is C1-C4 alkyl or NR3R4 wherein R3 and R4 are independently C1-C3 alkyl, R1 is hydrogen and R2 is wherein R5 is phenyl and R7 is defined as in claim 1, whenever prepared by the process of claim 5 or by an obvious chemical equivalent.

7. The process of claim 1 for preparing 1-dimethyl-aminosulfonyl-2-amino-6-(.alpha.-hydroxy-.alpha.-methylbenzyl)benzimida-zole which comprises reacting 1-dimethylaminosulfonyl-2-amino-6-benzoylbenzimidazole with methyl magnesium bromide followed by hydrolysis.

8. 1-Dimethylaminosulfonyl-2-amino-6-(.alpha.-hydroxy-.alpha.-methylbenzyl)benzimidazole, whenever prepared by the process of claim 7 or an obvious chemical equivalent.

9. The process of claim 1 for preparing 1-dimethyl-aminosulfonyl-2-amino-6-(.alpha.-methylenebenzyl)benzimidazole which comprises reacting 1-dimethylaminosulfonyl-2-amino-6-(.alpha.-hydroxy-.alpha.-methylbenzyl)benzimidazole with p-toluene-sulfonic acid.

10. 1-Dimethylaminosulfonyl-2-amino-6-(.alpha.-methylene-benzyl)benzimidazole, whenever prepared by the process of claim 9 or an obvious chemical equivalent.

11. The process of claim 1 for preparing 1-dimethyl aminosulfonyl-2-amino-6-(.alpha.-ethyl-.alpha.-hydroxybenzyl)benzimida-zole which comprises reacting 1-dimethylaminosulfonyl-2-amino-6-benzoylbenzimidazole with ethyl magnesium bromide followed by hydrolysis.

12. 1-Dimethylaminosulfonyl-2-amino-6-(.alpha.-ethyl-.alpha.-hydroxybenzyl)benzimidazole, whenever prepared by the process of claim 11 or an obvious chemical equivalent.

13. The process of claim 1 for preparing 1-dimethyl-aminosulfony}-2-amino-6-(.alpha.-ethylidenebenzyl)benzimidazole which comprises reacting 1-dimethylaminosulfonyl-2-amino-6-(.alpha.-ethyl-.alpha.-hydroxybenzyl)benzimidazole with p-toluene-sulfonic acid.

14. 1-Dimethylaminosulfonyl-2-amino-6-(.alpha.-ethyl-idenebenzyl)benzimidazole, whenever prepared by the process of claim 13 or an obvious chemical equivalent.

15. The process of claim 1 for preparing 1-dimethyl-aminosulfonyl-2-amino-6-(.alpha.-isopropyl-.alpha.-hydroxybenzyl)benzimi-dazole which comprises reacting 1-dimethylaminosulfonyl-2-amino-6-benzoylbenzimidazole with isopropyl magnesium chloride followed by hydrolysis.

16. 1-Dimethylaminosulfonyl-2-amino-6-(.alpha.-isopropyl-.alpha.-hydroxybenzyl)benzimidazole, whenever prepared by the process of claim 15 or an obvious chemical equivalent.

17. The process of claim 1 for preparing 1-dimethyl-aminosulfonyl-2-amino-6-(.alpha.-isopropylidenebenzyl)benzimidazole which comprises reacting 1-dimethylaminosulfonyl-2-amino-6-(.alpha.-isopropyl-.alpha.-hydroxybenzyl)benzimidazole with p-toluene-sulfonic acid.

18. 1-Dimethylaminosulfonyl-2-amino-6-(.alpha.-isopropyl-idenebenzyl)benzimidazole, whenever prepared by the process of claim 17 or an obvious chemical equivalent.

19. The process of claim 1 for preparing 1-iso-propylsulfonyl-2-amino-6-(.alpha.-hydroxy-.alpha.-methylbenzyl)benzimida-zole which comprises reacting 1-isopropylsulfonyl-2-amino-6-benzoylbenzimidazole with methyl magnesium bromide followed by hydrolysis.

20. 1-Isopropylsulfonyl-2-amino-6-(.alpha.-hydroxy-.alpha.-methylbenzyl)benzimidazole, whenever prepared by the process of claim 19 or an obvious chemical equivalent.

21. The process of claim 1 for preparing 1-iso-propylsulfonyl-2-amino-6-(.alpha.-methylenebenzyl)benzimidazole which comprises reacting 1-isopropylsulfonyl-2-amino-6-(.alpha.-hydroxy-.alpha.-methylbenzyl)benzimidazole with p-toluene-sulfonic acid.

22. 1-Isopropylsulfonyl-2-amino-6-(.alpha.-methylene-benzyl)benzimidazole, whenever prepared by the process of claim 21 or an obvious chemical equivalent.

23. The process of claim 1 for preparing 1-iso-propylsulfonyl-2-amino-6-(.alpha.-hydroxy-.alpha.-n-butylbenzyl)-benzimidazole which comprises reacting 1-isopropylsulfonyl-2-amino-6-benzoylbenzimidazole with n-butyl magnesium bromide followed by hydrolysis.

24. 1-Isopropylsulfonyl-2-amino-6-(.alpha.-hydroxy-.alpha.-n-butylbenzyl)benzimidazole, whenever prepared by the process of claim 23 or an obvious chemical equivalent.

25. The process of claim 1 for preparing 1-iso-propylsulfonyl-2-amino-6-(.alpha.-n-butylidenebenzyl)benzimidazole which comprises reacting 1-isopropylsulfonyl-2-amino-6-(.alpha.-hydroxy-.alpha.-n-butylbenzyl)benzimidazole with p-toluene-sulfonic acid.

26. 1-Isopropylsulfonyl-2-amino-6-(.alpha.-n-butylidene-benzyl)benzimidazole, whenever prepared by the process of claim 25 or an obvious chemical equivalent.

27. The process of claim 1 for preparing 1-iso-propylsulfonyl-2-amino-6-(.alpha.-hydroxy-.alpha.-isopropylbenzyl)benzimi-dazole which comprises reaction 1-isopropylsulfonyl-2-amino-6-benzoylbenzimidazole with isopropyl magnesium bromide followed by hydrolysis.

28. 1-Isopropylsulfonyl-2-amino-6-(.alpha.-hydroxy-.alpha.-isopropylbenzyl)benzimidazole, whenever prepared by the process of claim 27 or an obvious chemical equivalent.

29. The process of claim 1 for preparing 1-iso-propylsulfonyl-2-amino-6-(.alpha.-hydroxy-.alpha.-ethylbenzyl)benzimida-zole which comprises reacting 1-isopropylsulfonyl-2-amino-6-benzoylbenzimidazole with ethyl magensium bromide followed by hydrolysis.

30. 1-Isopropylsulfonyl-2-amino-6-(.alpha.-hydroxy-.alpha.-ethylbenzyl)benzimidazole, whenever prepared by the process of claim 29 or an obvious chemical equivalent.

31. The process of claim 1 for preparing 1-dimethyl-aminosulfonyl-2-amino-6-(.alpha.-hydroxy-.alpha.-n-propylbenzyl)benzimi-dazole which comprises reacting 1-dimethylaminosulfonyl-2-amino-6-benzoylbenzimidazole with n-propyl magnesium bromide followed by hydrolysis.

32. 1-Dimethylaminosulfonyl-2-amino-6-(.alpha.-hydroxy-.alpha.-n-propylbenzyl)benzimidazole, whenever prepared by the process of claim 31 or an obvious chemical equivalent.

33. The process of claim 1 for preparing 1-dimethyl-aminosulfonyl-2-amino-6-(.alpha.-hydroxy-.alpha.-n-butylbenzyl)benzimida-zole which comprises reacting 1-dimethylaminosulfonyl-2-amino-6-benzoylbenzimidazole with n-butyl magnesium bromide followed by hydrolysis.

34. 1-Dimethylaminosulfonyl-2-amino-6-(.alpha.-hydroxy-.alpha.-n-butylbenzyl)benzimidazole, whenever prepared by the process of claim 33 or an obvious chemical equivalent.

35. The process of claim 1 for preparing 1-dimethyl-aminosulfonyl-2-amino-6-(.alpha.-n-butylidenebenzyl)benzimidazole which comprises reacting 1-dimethylaminosulfonyl-2-amino-6-(.alpha.-hydroxy-.alpha.-n-butylbenzyl)benzimidazole with p-toluene-sulfonic acid.

36. 1-Dimethylaminosulfonyl-2-amino-6-(.alpha.-n-butyl-idenebenzyl)benzimidazole, whenever prepared by the process of claim 35 or an obvious chemical equivalent.

37. The process of claim 1 for preparing 1-iso-propylsulfonyl-2-amino-6-(.alpha.-ethylidenebenzyl)benzimidazole which comprises reacting 1-isopropylsulfonyl-2-amino-6-(.alpha.-hydroxy-.alpha.-ethylbenzyl)benzimidazole with p-toluene-sulfonic acid.

38. 1-Isopropylsulfonyl-2-amino-6-(.alpha.-ethylidene-benzyl)benzimidazole, whenever prepared by the process of claim 37 or an obvious chemical equivalent.