IE44863B1 - 2-(amino or acylamino)-1-sulphonyl-benzimidazole derivatives - Google Patents
2-(amino or acylamino)-1-sulphonyl-benzimidazole derivativesInfo
- Publication number
- IE44863B1 IE44863B1 IE259/77A IE25977A IE44863B1 IE 44863 B1 IE44863 B1 IE 44863B1 IE 259/77 A IE259/77 A IE 259/77A IE 25977 A IE25977 A IE 25977A IE 44863 B1 IE44863 B1 IE 44863B1
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- amino
- benzimidazole
- alkyl
- dimethylaminosulfonyl
- compounds
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
- C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
- C07D235/30—Nitrogen atoms not forming part of a nitro radical
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
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- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Communicable Diseases (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Virology (AREA)
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Abstract
Sulphonylbenzimidazole derivatives of formula wherein R2 represents 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 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 The compounds prepared may be used for the control of viruses.
Description
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 (Tyrell and Bynoe, 1966) indicated that 5 . 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.
X.. 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 l-dimethylaminosulfonyl-215 aminobenzimidazole compounds have been disclosed in U. S.
Patent 3,353,908.
- 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
-2wherein **8G3
R is C^-C4 alkyl, Gg-Cy cycloalkyl (as herein defined), thienyl, phenyl, or -NR^R^ wherein R3 and R4 are independently C^-C^ alkyl;
R^ is hydrogen, or G^-C^ acyl;
OH
I
R„ is Rr-C- or R.-C- ;
f J i 3 n
Rg Ry wherein Rg is C^-C^ alkyl, phenyl, halophenyl (as herein defined), or C3~Cg cycloalkyl (as herein defined);
!J Ry is C|-Cy alkylidene; and
Ry is at the 5 or 6 position.
The compounds of formula (I) are prepared by reacting a benzimidazole compound of the general formula
X5 wherein R and Rg are defined as before, with a C^-Cy alkyl magnesium halide or C,-Cy alkyl lithium, followed by hydrolysis to form the compounds of formula (X) wherein OH
I
Ry is Rjj-C- , optionally followed by dehydration to form the compounds of formula (I.) wherein R. is R.-C- , and/or
-3followed by acylation to obtain the compounds of formula (I) wherein is C^-C^ acyl.
A preferred group of compounds are the compounds of formula (I) wherein
R is C^-C^ alkyl or'-NRgR^ wherein Rg and are independently C^-Cg alkyl; and is hydrogen.
An especially preferred group of compounds are the compounds of formula (I) wherein
R is C^-C^ alkyl or -NRgR^ wherein Rg and are independently C^-Cg alkyl:
R^ is hydrogen; and
R9 is R_-C— ii
R?
wherein Rg is phenyl and K? is defined as before.
Illustrative of such preferred compounds are the
- following:
l-dimethylaminosulfonyl-2-amino-5(6)-(a-hydroxy20 α-n-pentylbenzyl)benzimidazole, l-dimethylaminosulfonyl-2-amino-5(6)-[a-hydroxya-(2,4-dimethyl-3-pentyl)benzyl]benzimidazole,
1-dimethylaminosulfonyl-2-amino-5(6)-(a-hydroxya-n-hexylbenzyl)benzimidazole,
1-dimethylaminosulfonyl-2-amino-5(6)-(a-hydroxya-sec-butylbenzyl)benzimidazole,
1-dimethylaminosulfonyl-2-amino-5(6)-(a-n-propylidenebenzyl) benzimidazole,
-4'i486 3 l-dimethylaminosulfonyl-2-amino-‘.> (6)- (α-n-penty1idenebenzyl)benzimdiazole, l-dimethylaminosulfonyl-2-amino-5(6)-(a-2,4dimethyl-3-pentylidenebenzyl)benzimidazole, l-dimethylaminosulfonyl-2-amino-5(6)-(a-n-hexylidenebenzyl)benzimidazole, l-dimethylaminosulfonyl-2-amino-5(6)-(a-secbuty1idenebenzy1) ben z imidazole, l-isopropylsulfonyl-2-amino-6-a-isopropylidenebenzylbenzimidazole, l-isopropylsulfonyl-2-amino-5(6)-[a-hydroxy-a(2,4-dimethyl-3-pentyl)benzyl]benzimidazole, and l-isopropylsulfonyl-2-amino-5(6)-(a-2,4-dimethyl3-pentylidenebenzy1)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.
6&S6'
The term C^-C^ alkyl refers to methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl. The term C^-C^ alkyl includes within its definition the terms C^-C^ alkyl.2 The term C^-C? 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-dimethyl3-pentyl, t-butyl and neopentyl,
The term Cg-Cgand Cg-C?
cycloalkyl refers 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 C^-C^ acyl refers to the straight and branched chain aliphatic acyl radicals of one to four carbon atoms such as formyl, acetyl, propionyl, butyryl, and 2methylpropionyl .The term C^-C^ alkylidene refers to straight and branched radicals of one to seven carbon atoms such as methylene, ethylidene, propylidene, isopropylidene, butylidene, isobutylidene, 3-methyl-2-butylidene, 2,4-dimethyl-3pentylidene, and n-hexylidene.
-6<5 4863
In the above process suitable dehydration agents are strong acids, such as g-toluenesulfonu· acid, sulfuric acid, trifluoroacetic acid, methanesulfonic acid, or trifluoromethanesulfonic acid. The C^-C^ alkyl magnesium halide is an appropriate Grignard reagent. The C^-C^ 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 Patent Specification No. 43531
The product of the reaction is a 1-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 sulfonylbenzimidazole 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.
-74 3
The 5(6)-isomers are separable by fractional crystallization: or by column chromatography. Usually the 6-isomer crystallizes first from a solution of the mixture.
The 2-acylamino sulfonylbenzimidazoles wherein R^ . 5 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-tocharge 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 IN hydrochloric acid, extracted twice with diethyl ether, washed with saturated sodium chloride, dried, ahd filtered to yield 2.9 g., as an amorphous solid, of 1dimethylaminosulfonyl-2-amino-6-(a-hydroxy-a-methylbenzyl)benzimidazole, m/e 360.
-8<*4863
Analysis c17H2oN4°3s MW 360
Calcd: C, 56.67; II, 5.59; N, 15.54
Found: C, 56.77; H, 5.46; N, 15.27 Example 2
Two grains (5.5 mmole! of 1-dimethylaminosulfonyl2-amino-6-(α-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-dimethylaminosulfonyl-2-amino-6-(α-methylenebenzyl)benzimidazole, m.p. 201-202°C.
Analysis C37H^gN4O.,i 5 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-6-benzoylbenzimidazole, there was obtained 3.2 g., as a foam, of 1-dimethylaminosulfonyl-2-amino-6-(α-ethyl-a-hydroxybenzyl)benzimidazole.
High resolution mass spec, for C£giI22N4°3S
Calcd: 374.14123
Found: 374.141
-9080- ..EXample 4
When the procedure of Example 2 was repeated using 1.2 g. (3.21 mmole) of l-dimethylaminosulfanyl-2amino-6-(a-ethyl-a-hydroxyben2yl)benzimidazole, 750 mg. of £-toluenesulfonic acid, and 100 ml. of chloroform, there was obtained 388 mg. Of l-dimethylaminosulfonyl-2-antino-6(α-ethylidenebenzyl)benzimidazole, rii.p. 200-202°C. (dec.)
High resolution mass spec, for C18H2ON4°2S Calcd: 356.13107
Found: 356.131
Example 5
When the procedure of Example 1 was repeated using 4.1 g. (12 mmole) of l-dimethylaminosulfonyl-2amino-6-benzoylbenzimidazole 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-(α-isopropyl-a-hydroxybenzyl)benzimidazole, yield 65%.
Example 6
When the procedure of Example 2 was repeated using
1.2 g. (3.2 mmoles) of l-dimethylaminosulfonyl-2-amino6-(α-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-dimethylaminosulfonyl-2-amino-6- (α-isopropylidenebenzyl)benzimidazole.
-1044863
Example Ί
To a solution of 150 ml. of tctrahydrofuran and 31 ml. (84 mmole) of methyl magnesium bromide in diethyl ether, under nitrogen, was added dropwise a solution of
.0 g. (15 mmole) of l-isopropylsulfonyl-2-amino-6-benzoylbenzimidazole in 200 ml. of tetrahydrofuran. The mixture was stirred at 25°C. for 1 hour, refluxed for 2 hours, cooled, poured into ice and IN 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 v/as recovered by concentration of the filtrate under vacuum, yield 2 g. The product was 1-isopropylsulfonyl2-amino-6-(α-hydroxy-a-methylbenzyl)benzimidazole, m/e 360,
344 base.
Analysis 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 l-isopropylsulfonyl-2amino-6-(α-hydroxy-a-methylbenzyl)benzimidazole in 100 ml. of chloroform was reacted with 1.3 g. of £-toluenesulfonic acid. The solution was refluxed with stirring for 4 hours.
-11¢¢863
The solution was cooled to 25’C,, 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, l-isopropylsulfonyl-2-amino~6-(a-methylenebenzyl)benzimidazole, m.p. 147-143°C. m/e 341.
Analysis cxgHxgN3°2S W 341 Calcd: C, 63.32; H, 5.61; N, 12.31 Found: C, 63.55; H, 5.53; N, 12.15
Example 9
When the procedure of Example 7 was repeated using
150 ml. of tettahydrofuran, 31 ml. (84 mmole) of n-butyl magnesium bromide, 5.0 g. (15 mmole) of 1-isopropylsulfonyl2-amino-6-benzoylbenzimidazole, and refluxing for 20 hours,
' there was obtained 5.0 g., as a tan foam, of 1-isopropylsulfonyl-2-amino-6“(α-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; W, 10.17
Example 10
When the procedure of Example 8 was repeated using
g. (2.5mmole)ofl-is0propylsulfonyl-2-amino-6-(a-hydroxyα-n-butylbenzyl)benzimidazole, 75 ml. of chloroform, 600 mg. of g-toluenesulfonic acid, and refluxed for 90 minutes, there was obtained 790 mg. of l-isopropylsulfonyl-2-amino6-(a-n-butylideneben2yl)benzimidazole.
Analysis C2xH25N3°2S MW 383 Calcd: C, 65.77; H, 6.57; H, 10.96 Found: C, 65.49; H, 6.31; N, 10.78
-1244863
Example 11
When the procedure of Example 7 was repeated using 40 ml. (85 mmole) of isopropyl magnesium bromide,
.0 g. (15 mmole) of l-isopropylsul£onyl-2-amino-6-benzoyl5 benzimidazole and 200 ml. of tetrahydrofuran, there was obtained, as a yellow foam, 5.0 g. of 1-isopropylsulfonyl2-amino-6-(α-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 l-isopropylsulfonyl-2-amino-6benzoylbenzimidazole, and 150 ml. of tetrahydrofuran, there was obtained, as a beige foam, 4.6 g. of l-isopropylsulfohyl15 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-isopropylsulfonyl-2-amino-620 (α-hydroxy-a-ethylbenzyl)benzimidazole, 50 ml. of chloroform, and 600 mg. of g-toluenesulfonic acid, there was obtained, as an amorphous foam, 630 mg. of 1-isopropylsulfonyl“2-amino-6-(α-ethylidenebenzyl)benzimidazole.
-13Analysis 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 ml. (60 mmole) of n-propyl 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 l-dimethylaminosuifonyl-2-amino-6-(a-hydroxy-a-n-propylbenzylj 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 l-dimethylaminosulfonyl-2-amino-6benzoylbenzimidazole in 90'ml. of tetrahydrofuran, there was obtained, as a white foam, 1.7 g. of 1-dimethylaminosulfonyl2-amino-6-(a-hydroxy-a-n-butylbenzyl)benzimidazole. m/e 402.
- - t Example 1620 When the procedure of Example 2 was repeated using
402 mg. of l-dimethylaminosulfonyl“2-amino-6-(α-hydroxy-an-butylbenzyl) benzimidazole in 20 ml. of chloroform, 234 mg. of p-toiuenesulfonic acid, and 100 ml. of chloroform, there was obtained 302 mg. of l-dimethylamittosul£onyl-2-amino-625 (a-n-butylideneben2yl)benzimidazole, m/e 384.
-14448G3
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 37°C. in medium 199 with 5 percent inactivated fetal bovine serum (FBS), penicillin (150 units 1 ml.) and streptomycin (150 meg./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 i percent lonagar No. 2 (Registered Trade Mark) and one part double strength itedium 199 with FBS, penicillin, and streptomycin which contains drug at concentrations of 100, 50, 25, 12, 6, 3 and 0 micro-15448 s 3 grams; per milliliter (meg./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 meg./ml. The flasks were incubated for 72 hours at 37°C. for polio, Coxsackie, echo, and Mengo virus and 120 hours at 32°C. for rhinovirus.- Plagues 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 Ι^θ.
ι
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 1-4), 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
-1644863 examples, column 2 gives the 5(6)-posit ion 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.).
-17448 S3
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 (1) 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, apacia 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.
-19The compounds can also be mixed with a liquid and administered as nose drops or intranasal spray.
Claims (10)
1. Ι. A sulfonyl benzimidazole compound of the general formula 5 wherein R is C 1 -C 4 alkyl, Cg-C 7 cycloalkyl, (as herein defined), thienyl, phenyl, or wherein R 3 and R^ are independently Cg-Cg alkyl; Rg is hydrogen, or Cg-C^ acyl; OK I 10 R 2 is or R^-C- ; R g R ? wherein Rg is alkyl, phenyl, halophenyl, (as herein defined), or Cg-C g cycloalkyl (as herein defined); Rg is Cg-Cg alkyl; R ? is Cg-Cg alkylidene; and 15 Rg is at the 5 or 6 position.
2. A compound of claim 1 wherein R is Cg-C 4 alkyl or -NRgR^ wherein Rg and R^ are independently Cg-Cg alkyl; and Rg is hydrogen. -215 S' 3.
3. A compound of Claim 2 wherein R- ia Rfc-e2 5 ο wherein Rg is phenyl and R? is defined as in claim 1. 4.
4. Any one of the following compounds of claim Is l-dimethylaminosulfonyl~2-amino-6-(a-hydroxy-amethylbenzyl)benzimidazole l-dimethylaminosulfonyl-2-amino-6-(a-methylene10 benzyl)benzimidazole l-dimethylaminosulf0nyl-2-amino-6-(a-ethyl-ahydroxybenzyl) benzimidazole l-dimethylaminosulfonyl-2-amino-6-(a-ethylidenebenzyl)benzimidazole 15 l-dimethylaminosulfonyl-2-amino-6-(α-isopropyl- . a-hydroxybenzyl)benzimidazole l-dimethylaminosulfonyl-2-amino-6-(a-isopropylidenebenzyl)benzimidazole l-isopropylsulfOnyl-2-amino-6-(a-hydroxy-α20 methylbenzyl)benzimidazole --, l-isopropylsulfonyl-2-amino-6-(α-methylenebenzyl)benzimidazole 1-isopropylsulfonyl-2-amino-5-ίa-hydroxy-a-nbutylbenzyl)benzimidazole 25 l-isopropylsulfonyl-2-amino-6-(a-n-butylidenebenzyl)benzimidazole l-isopropylsulfonyl-2-amino-6-(a-hydroxy-aisopropylbenzyl) benzimidazole -224 4 8 6 3 l-isopropylsul£onyl-2-amino-6-(α-hydroxy-aethylbenzyl)benzimidazole l-isopropylsulfonyl-2-amino-6-(α-ethylidenebenzyl)benzimidazole 5. L-dimethylaminosulfonyl-2-amino-6-(a-hydroxy-an-propylbenzyl)benzimidazole l-dimethylaminosulfonyl-2-amino-6-(a-hydroxy-an-butylbenzyl)benzimidazole l-dimethylamino3ulfonyl-2-amino-6-(a-n-butyl10 idenebenzyl)benzimidazole
5. A process for preparing the compounds of claim 1 which comprises reacting a compound of the general formula SO R z 15 wherein R and Rg are defined as in claim 1, with a C^-C^ alkyl magnesium halide or C^-C^ alkyl lithium, followed by hydrolysis to form the compounds of claim 1 wherein OH I Rj is Rg-C- , optionally followed by dehydration to form *6 the compounds of claim 1 wherein is Rg-C- , and/or Ry 20 followed by acylation to obtain the compounds of claim 1 wherein is C^-C^ acyl. -234
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 5 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
10. 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.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US05/750,991 US4118742A (en) | 1975-08-28 | 1976-12-15 | Carbonyl-substituted 1-sulfonylbenzimidazoles |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| IE44863L IE44863L (en) | 1978-06-15 |
| IE44863B1 true IE44863B1 (en) | 1982-04-21 |
Family
ID=25019992
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IE259/77A IE44863B1 (en) | 1976-12-15 | 1977-02-08 | 2-(amino or acylamino)-1-sulphonyl-benzimidazole derivatives |
Country Status (26)
| Country | Link |
|---|---|
| JP (1) | JPS5377062A (en) |
| AR (1) | AR225397A1 (en) |
| AT (1) | AT347937B (en) |
| AU (1) | AU509374B2 (en) |
| BE (1) | BE851630A (en) |
| BG (1) | BG27742A3 (en) |
| CA (1) | CA1079737A (en) |
| CH (1) | CH630368A5 (en) |
| CS (1) | CS190339B2 (en) |
| DD (1) | DD129445A6 (en) |
| DE (1) | DE2706227A1 (en) |
| DK (1) | DK145645C (en) |
| ES (1) | ES456090A1 (en) |
| FR (1) | FR2374311A2 (en) |
| GB (1) | GB1568543A (en) |
| GR (1) | GR66420B (en) |
| HU (1) | HU175361B (en) |
| IE (1) | IE44863B1 (en) |
| IL (1) | IL51445A (en) |
| MX (1) | MX4495E (en) |
| NL (1) | NL187396C (en) |
| PL (1) | PL106887B1 (en) |
| RO (1) | RO71886A (en) |
| SE (2) | SE433351B (en) |
| SU (1) | SU680645A3 (en) |
| ZA (1) | ZA77691B (en) |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4420479A (en) * | 1982-04-08 | 1983-12-13 | Eli Lilly And Company | Olefinic benzimidazoles, formulations, and antiviral methods |
| FR2593177B1 (en) * | 1986-01-20 | 1988-04-01 | Novapharme | NEW BENZIMIDAZO |
| US5693661A (en) * | 1995-06-07 | 1997-12-02 | Eli Lilly And Company | Anti-viral compounds |
| JP7226480B2 (en) | 2020-07-30 | 2023-02-21 | 大日本印刷株式会社 | Antiviral article and antiviral resin composition |
| JPWO2022059676A1 (en) | 2020-09-18 | 2022-03-24 |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS51125078A (en) * | 1974-07-01 | 1976-11-01 | Lilly Co Eli | Production of substituted 11sulphonylbenzimidazole |
-
1977
- 1977-02-07 GR GR52736A patent/GR66420B/el unknown
- 1977-02-07 ZA ZA00770691A patent/ZA77691B/en unknown
- 1977-02-08 CA CA271,307A patent/CA1079737A/en not_active Expired
- 1977-02-08 IE IE259/77A patent/IE44863B1/en not_active IP Right Cessation
- 1977-02-09 GB GB5254/77A patent/GB1568543A/en not_active Expired
- 1977-02-14 IL IL51445A patent/IL51445A/en unknown
- 1977-02-14 DE DE19772706227 patent/DE2706227A1/en active Granted
- 1977-02-17 RO RO7789438A patent/RO71886A/en unknown
- 1977-02-17 NL NLAANVRAGE7701715,A patent/NL187396C/en not_active IP Right Cessation
- 1977-02-18 AT AT111277A patent/AT347937B/en not_active IP Right Cessation
- 1977-02-18 AU AU22440/77A patent/AU509374B2/en not_active Expired
- 1977-02-18 JP JP1769877A patent/JPS5377062A/en active Granted
- 1977-02-18 SE SE7701845A patent/SE433351B/en not_active IP Right Cessation
- 1977-02-18 MX MX775442U patent/MX4495E/en unknown
- 1977-02-18 BE BE1007954A patent/BE851630A/en not_active IP Right Cessation
- 1977-02-18 DD DD7700197445A patent/DD129445A6/en unknown
- 1977-02-18 HU HU77EI729A patent/HU175361B/en unknown
- 1977-02-18 FR FR7704799A patent/FR2374311A2/en active Granted
- 1977-02-18 CS CS771093A patent/CS190339B2/en unknown
- 1977-02-18 CH CH207577A patent/CH630368A5/en not_active IP Right Cessation
- 1977-02-18 DK DK73277A patent/DK145645C/en not_active IP Right Cessation
- 1977-02-18 BG BG035460A patent/BG27742A3/en unknown
- 1977-02-18 ES ES456090A patent/ES456090A1/en not_active Expired
- 1977-02-18 SU SU772452269A patent/SU680645A3/en active
- 1977-02-18 AR AR266611A patent/AR225397A1/en active
- 1977-02-19 PL PL1977196131A patent/PL106887B1/en unknown
-
1980
- 1980-11-18 SE SE8008090A patent/SE433352B/en not_active IP Right Cessation
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Legal Events
| Date | Code | Title | Description |
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| MK9A | Patent expired |