CS202562B2 - Process for preparing 1-sulphonylbenzimidazoles substituted on carbonyl group - Google Patents

Description

'The incidence of upper respiratory tract viral diseases is currently large, it was. determined that in the United States alone, there are almost a trillion diseases per year. Statistics conducted in the United Kingdom (Týrali á Bynoc, Lancet 1, 16, 1966) show that 74% of people with upper respiratory tract infection were infected with rhinoviruses. Since more than 80 strains of rhinoviruses are known, vaccination is almost impractical, so chemotherapy ^: is likely to be the only possible solution.

The ability of chemicals to inhibit the growth of viruses in vitro can be demonstrated by using non-active cancan cultures (viral-induced staining and plaque formation as described in Siminoff, Applied Microbiology, 9 (1) 66 (1981).

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

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

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

where

R is C 1 -C 4 alkyl or-NR 1 R 1 -R 1 in which R 3 is C 1 -C 4 alkyl;

R 8 and R 8, the same or different, are alkyl of 1 to 3 carbon atoms,

R2 is 1,3,4-oxadiazol-2-yl, in the 5 or 6 position, characterized in that a compound of formula II is reacted

where

R 2 is as defined above and.

R 1 represents alkoxymethylene of 1 to 3 carbon atoms in the alkyl moiety with an acid at room temperature.

The term "tautomeric banzimidazole" refers to banzimidazole which may be substituted on any nitrogen atom by a hydrogen atom. Benzimildazole, unsubstituted by n, and a nitrogen atom and substituted in the 5-position of the benzene ring has the corresponding tautomeric form in which the same substituent is in the 6-position. The mixture of these isomers can be designated ‘9 (6). As a result of this tautomerism, the reaction of 5 (6) -substituted benzimidazole with the sulfonyl chloride of formula III results in an isomeric mixture of 5 (6) -substituted sulfonylbenzimidazoles.

The term "1,3,4-oxadiazol-2-yl" refers to the 1,3,4-oxadiazole moiety bound at the 2-position.

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

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

Benzimidazole derivatives with 9 (6) -substituents which do not react with the sulfonyl chloride under the reaction conditions are preferred The benzimidazole derivatives and the sulfonyl chloride are generally used in approximately equimolar amounts, although a small excess of either may be used. a wide variety of non-reactive solvents such as acetone, tetrahydrofuran, tertiary amides such as Ν, Ν-dimethylformide and chlorinated hydrocarbons such as dichloromethane, dichloroethane and chloroform The reaction medium may also contain a base as an acid binding agent. pyridine, triethylamine, N-methylmorpholine, sodium hydrogen carbonate and sodium hydride The preferred solvent is acetone containing a diethylamine or tetrahydrofuran with dimethylformamide and containing sodium hydride as the base.

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

The product of the reaction is a 1-sulfonylbenzimidazole derivative, hereinafter referred to as the sulfonylbenzimidazole derivative. The product can be isolated by filtration of the reaction mixture and concentration of the filtrate to obtain crystallization. The reaction mixture can also be evaporated to dryness and the residue dissolved in a suitable solvent such as acetone or methanol to separate and remove insoluble material. The solution containing the sulfonylbenzimidazole derivative is concentrated to obtain crystallization or re-evaporated to dryness and the second residue is then dissolved, for example, in methanol, from which the resulting product is obtained by crystallization.

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

Certain compounds of Formula I may be prepared by chemical methods such as acylation, oxidation, or reduction of the corresponding sulfonyl benzimidazole precursor. When the reaction is carried out on a precursor which is an isomeric mixture of sulfonylbenzimidazoles, the isomeric products may be separated from each other by fractional crystallization or chromatography. :

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

Ethyl esters of sulfonylbenzimidazolecarboxylic acids or Isomeric mixtures of these ethyl esters can be reacted with hydrazine in carbinol to give the corresponding hydrazides. For example, ethyl 1-dimethylaminosulfonyl-2-amino-5 (6) -benzimidazole carboxylate can be refluxed with hydrazine hydrate in methanol to give 1-dimethylaminosulfonyl-2-amino-5 (6) -benzimidazolecarboxylic acid hydrazides . The hydrazides can be converted to the corresponding 5 (6H1,3,4-oxadiazol-5-yl) sulfonylbenzimidazoles by heating at a higher temperature with orthoesters such as ethyl orthoformate as shown in Reaction Scheme I. For example, when 1-dimethylaminosulfonyl acid hydrazide is heated 2-acetamido-5 (6) -benzimidazolecarboxylic acid at reflux temperature and ethyl orthoformate gave 1-dimethylaminosulfonyl-2-acetamido-5 (6) - (1,3,4-oxadiazol-5-yl) benzimidazole.

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

Reaction Scheme I

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

where

R 2 'means lower alkyl, cycloalkyl, phenyl or substituted with halogen, lower alkyl or lower alkoxy.

The process consists in ammonolysis and reduction of 4-halo-3-nitrophenyl ketone, which is prepared by Friedel-Crafts reaction of 1) 4-halo-3-nitrobenzoyl chloride with the appropriate hydrocarbon or 2) halobenzene with the appropriate acid chloride followed by aromatic nitration. Ketobeinzimidazoles can also be prepared from acetanilide by Friedel-Crafts acylation with an appropriate alkanoic acid derivative of 2 to 8 carbon atoms. The resulting 4-ketoacetanilide is filtered to give 2-nitro-4-ketoacetanilide. This acetanilide is then hydrolyzed to 2-nitro-4-ketoaniline. The nitroaniline is catalytically hydrogenated to 4-keto-o-phenylenediamine, which is subjected to ring closure to give 2-substituted 5 (6) -ketobenzimidazole. However, the ketocarbonyl function is less reactive than the carboxaldehyde function. Ketofunction can be activated by protonation of the sulfonylbenzimidazole compound under acidic conditions, thereby easily forming a double bond between the carbon and nitrogen atoms.

Sulfonylbenzimidazole compounds wherein R 2 is a heterocyclic group, for example tetrazole, can be obtained as follows. Generally, 5 (6) - (1-alkylthetrazol-3-yl) sulfonylbenzimidazole derivatives of formula (I) and 2-substituted 5 (6) - (1-alkylthetrazol-5-yl) benzimidazole derivatives may be prepared such that 4- the aminobenzonitrile is acetylated and nitrated to 3-nitro-4-acetamidobenzonitrile. Benzonitrile is reacted with sodium azide in dimethylformamide in the presence of ammonium chloride to give 5- (3-nitro-4-acetamidophenyl) tetrazole. The tetrazole group is alkylated with methyl iodide in acetone and triethylamine to give 1- (2) -methyl-5- (3- The isomeric mixture of tetrazole is hydrolyzed with concentrated sulfuric acid at room temperature for several hours to give 1- (2) -methyl-5- (3-nitro-5-aminophenyl) tetrazole. The benzene ring is hydrogenated in a mixture of ethanol and ethyl acetate at 30 ° C in the presence of palladium on charcoal to give 1- (2) -methyl-5- (3,4-diaminophenyl) -tetrazole. a mixture of methanol and water to form the substantially single me202562 thylated isomer, 2-amino-5 (6) (1-methyltetrazol-5-yl) benzimidazole, which is reacted with dimethylsulfamoyl chloride in acetone in the presence of triethy hylamine, the product being 1-dimethylaminosulfonyl-2-amino-5 (6) - (1-methyltetrazol-5-yl) benzimidazole.

Using the appropriate 2-substituted 5 (6) - (1-alkylthetrazol-5-yl) benzimidazole as the reactant and the corresponding sulfonyl chloride as described above, additional 5 (6) - (1-alkylthetrazol-5-yl) sulfonylbenzimidazole derivatives can be obtained I.

The benzimidazole compounds which are the starting materials for carrying out the process according to the invention can be obtained by a number of known methods. The preparation of a variety of benzimidazoles is well described in Weissberger's The Chemistry of Heterocyelic Compounds, Imidazole and Its Derivatives, Interscience Publishers Co., New York., 1953. 2-Aminobenzimidazole derivatives can be obtained by cyclization of the appropriate o-phenylenediamine with cyanogen bromide as described in Buttle et al., Bio. Chem. J. 32, 1101 (1938) and British Patent No. 551,524. The preparation of ethyl 2-amino-5 (6) -benzimidazole carboxylate is described in Paget et al., J. Med. Chem. 12, 1010 (1969).

Of the sulfonyl chlorides which are preferred reactants, methanesulfonyl chloride (mesyl chloride), isopropylsulfonyl chloride, dimethylsulfamoyl chloride, benzenesulfonyl chloride and 2-thiophenesulfonyl chloride are commonly supplied. Further alkylsulfonyl chlorides having 1 to 4 carbon atoms in the alkyl moiety can be obtained by chlorination of the corresponding alkylthiol or by reaction of sulfuryl chloride with sodium alkyl sulfonate derived from the corresponding carbinol and sulfuric acid.

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

R5R1N-CI with sulfur dioxide at -5 to 30 ° C. The chloramine derivatives are obtained by reacting the corresponding secondary amine with antimony chloride, sodium hypochlorite or sulfuryl chloride.

Another example of sulfonyl chlorides which can be used to react with benzimidazole compounds is ethyl, propyl, and the like. isopropyl-, butyl-, isobutyl-, sec-butyl- and tert-butylsulfonyl chloride.

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

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

Preferred sulfonylbenzimidazoles are those compounds of formula I wherein R is isopropyl or dimethylamino.

An example of a derivative of formula (I) is 1-isopropanesulfonyl-2-amino-5 (6) - (1,3,4-oxadiazol-2-yl) benzimidazole.

The following examples describe the practice of the process of the invention and the products of formula I. The term "m / e" used in the product characterization refers to the ratio of ions as they appear in the mass spectrum of the product relative to the starting material used. Usually these values correspond to the molecular weights of the major peaks.

He did

1-Dimethylaminosulfonyl-2-amino-5 (6) - (1,3,4-oxadiazol-2-yl) benzimidazole

A) 1-Dimethylaminosulfonyl-2-amino-5 (6) -benzimidazolecarboxylic acid hydrazide, ethyl 1-dimethylaminosulfonyl-2-amino-5 (6) -benzimidazolecarboxylate, 50 ml of methanol and 6 ml of hydrazine hydrate are heated to boiling under 100 hours. The hydrazide crystallizes out of solution during the reaction. The hot reaction mixture was filtered to give 200 mg of 1-dimethylaminosulfonyl-2-amino-5 (6) -benzimidazolecarboxylic acid as the hydrazide, m.p. 229-230 ° C with decomposition. The structure was confirmed by NMR spectrum.

For C10H14N6O3S (298) calculated:

% C, 40.30;% H, 4.70;% N, 28.20; found:

H, 4.54; N, 28.33.

After cooling the filtrate, a solid is obtained which is collected. This solid is an isomeric mixture of hydrazides of said acid. Two fractions of crystals were obtained from the filtrates after concentration and cooling of the solution, yielding a total of 350 mg of 1-dimethylaminosulfonyl-2-amino-6-benzimidazolecarboxylic acid hydrazide hydrate, m.p. 205-206 ° C. The structure was confirmed by NMR spectrum.

For C10H14N6O3S.H2O (316) calculated:

% C, 37.97;% H, 5.06;% N, 26.58;

τη o I pi ·

% C, 38.40;% H, 4.41;

Β) 1-dimethylaminosulfonyl-2-amino-5 (6) - (1,3,4-oxadiazol-2-yl) benzimidazole g (0.01 mol) 1-dimethylaminosulfonyl-2-amino-5 (6) -Benzimidazolecarboxylic acid and 100 ml of ethyl orthoformate are heated at reflux for 24 hours using a Dean-aged apparatus, the reaction mixture is evaporated to dryness in vacuo, the residue is dissolved in ethyl acetate and the product is crystallized by concentration and cooling to give 580 mg of 1-dimethylaminosulfonyl-2- (ethoxymethyleneamino) -5 (6) - (1,3,4-oxadiazol-2-yl) benzimidazole.

Calculated for C 14 H 18 N 3 O 16 S (364):

% C, 46.15;% H, 4.40;% N, 23.08; found *

H, 4.38; N, 22.64.

C) 1-dimethylaminosulfonyl-2-amino-5 (6) - (1,3,4-oxadiazol-2-yl) benzimidazole

580 mg of 1-dimethylaminosulfonyl-2- (ethoxymethyleneamino) -5 (6) - (1,3,4-oxadiazol-2-yl) benzimidazole was stirred for 1 hour at room temperature in 10 ml of 1 N hydrochloric acid. The reaction mixture was filtered to give 230 mg of 1-dimethylaminosulfonyl-2-amino-5 (6) - (1,3,4-oxadiazol-2-yl) benzimidazole hydrochloride, m.p. 200 DEG C. with decomposition.

For C11H12N6O3S.HCI (344.5) calculated:

% C, 38.32;% H, 3.80;% N, 24.38; found:

% C, 38.54;% H, 4.07;% N, 61.61.

The filtrate from step C) is mixed with sodium carbonate which is added until the solution is basic to litmus. A solid precipitated which was collected by filtration to give 120 mg of 1-dimethylaminosulfonyl-2-amino-5 (6) - (1,3,4-oxadiazol-2-yl) benzimidazole, m.p. 231 DEG C. with decomposition.

For C11H12N6O3S (308) calculated:

H, 4.19; N, 27.03. found:

H, 3.92; N, 27.26.

The compounds of formula I have a broad spectrum of antiviral activity. They are particularly effective in inhibiting the growth of echo, Mengo, Coxsackke (A9, 21, B5), polioviruses (type I, II, III) or rhinoviruses (25 strains), but also inhibit various types of influenza viruses such as Ann Arbor, Maryland B ,

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

Experimental methods

Monkey kidney cells (BSC-1) or Hela-cells (5-3) were grown in 25 ml Falcon flasks at 37 ° C in 199 and 5% inactivated fetal bovine serum (FBS) with penicillin in 150 units per ml and streptomycin at 150 micrograms per ml. Once a single cell layer is formed, the culture medium is removed and 0.3 ml of the appropriate dilution of the selected virus (echo, Mengo, Coixsackie, poliovirus or rhinovirus) is added to each flask. After absorption for one hour at room temperature, the infected cell layer is overlaid with an environment consisting of 1 part 1% Ionagar # 2 and 1 part double-concentrated medium 199 with FBS, penicillin and streptomycin and 100% active substance content, 50, 25, 12, 6, 3 and 0 micrograms per ml. A bottle that does not contain the active substance is a control bottle. Stock solutions of thiazolinobenzimidazole compounds or thiazinylbenzimidazole compounds of formula I were prepared in dimethylsulfoxide at a concentration of 10 ⁴ micrograms / ml. The bottles were incubated for 72 hours at 37 ° C for poliovirus and Coxsackie, echo and Mengo viruses and for 120 hours at 32 ° C for rhinovirus. Ann Arbor influenza virus, Maryland B, Massachusetts B, Hong Kong A, Pr-8a, and Taylor C (types A, B) were incubated for 72 hours at 37 ° C using MDCK cells (Medin-Darby dog kidney cells). Plaques could be observed in areas where virus multiplication occurred in cells. A solution of 10% formaldehyde and 2% sodium acetate was added to each flask to inactivate the virus and fix the cell layer to the surface of the substances. The plaques formed by the virus, regardless of their size, were counted after staining the surrounding areas with crystal violet. The number of coatings was compared to the number of plaques in the control bottle for each active agent concentration. The efficacy of the test substance was expressed as a percentage reduction in plaque count. That is, the concentration of the active ingredient I50 denotes the concentration that inhibits plaque formation by 50%. This concentration is a general measure of the effectiveness of the individual substances.

The results of the experiments are expressed by conversion to poliovirus type I, since this virus is easy to grow and reproducible results can be obtained. However, the efficacy of the compounds of the formula I has also been demonstrated for other vi202562 cultures, for example for Coxsackie viruses (A9, A21, B5), echo virus (strains 1-4), Mengo virus, rhinovirus (25 strains), poliovirus (type I, II). III) and influenza viruses such as Ann Arbor, Maryland B, Massachusetts B, Hong Kong A, Pr-8a and Taylor C (type A, B). The results for the various benzimidazole compounds of formula (I) are summarized in Table I. In the first column, there is ¹ example number, in the second column isomer type, columns 3 to 10 show plaque reduction at different drug dilutions ranging from 0.75 to 100. micrograms / ml.

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The 1-thiazolinylbenzimidazole compounds were investigated in pure form as a mixture of isomers. Both isomers inhibit the growth of the virus, with the 6-isomer usually more potent than the 5-isomer.

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

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

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

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

Claims (1)

pRedmít A process for the preparation of carbonyl-substituted 1-sulfonylbenzimidazoles of the general formula _; AND VYNALEZU R2 is 1,3,4-oxadiazol-2-yl, in the 5 or 6 position, characterized in that the reaction is carried out by reacting a compound of formula (II): R is C 1 -C 4 alkyl or -NR 3 R 4 in which R 3 is C 1 -C 4 alkyl; R 3 and R 4, the same or different, denote alkyl having 1 to 3 carbon atoms, (II) wherein R 2 is as defined above and R 1 is alkoxymethylene of 1 to 3 carbon atoms in the alkyl moiety with an acid at room temperature.