CS202560B2 - Process for preparing 1-sulphonylbenzimidazoles substituted on carbonyl group - Google Patents

Description

The incidence of upper respiratory tract viral diseases is currently high, with only a trillion diseases per year reported in the United States alone. Statistics in the United Kingdom (Tyrell and Bynoe, 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 impossible to control, 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 tissue cultures that do not produce virus-induced stains and plaques as described in Siminoff, Applied Microbiology, 9 (1), 66 (1961) ).

Some 1-dimethylaminosulfonyl-2-aminobenzimidazoles having antifungal activity have been described in US 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.

The present invention provides a process for the preparation of novel 1-sulfonylbenzimidazoles substituted on a carbonyl group of formula (I)

(I) where

R is alkyl of 1 to 4 carbon atoms or the group -NR 3 R 4 in which R 3 and R 4 are the same or different, are alkyl of 1 to 3 carbon atoms,

R2 is 1- (alkyl) tetrazol-5-yl of 1 to 3 carbon atoms in the 5 or 6 position of the alkyl moiety, characterized in that the compound of formula II is reacted

H

(II) where

R 2 represents alkylthetrazol-5-yl of 1 to 3 carbon atoms in the alkyl moiety, with a sulfonyl chloride of formula III, RSO 2 Cl (III), wherein

R is as defined above, in the presence of an organic solvent at room temperature to reflux.

The term "tautomeric benzimidazole" refers to benzimidazole, which may be substituted on any nitrogen atom by a hydrogen atom. The benzimidazole, unsubstituted at the 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 5 (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- (alkyl) tetrazol-5-yl" refers to a Ι-methyl-, 1-ethyl- or 1-propyltetrazole moiety bound at the 5-position.

The term "C 1 -C 4 alkyl" refers to straight or branched chain aliphatic radicals of 1 to 4 carbon atoms, namely 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 alkylcarbinol" 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.

Preferred reactants are benzimidazole derivatives with 5 (6) -substituents which do not react with the sulfonyl chloride under the reaction conditions. Benzimidazole derivatives and sulfonyl chloride are generally used in approximately equimolar amounts, although a small excess of either may be used. The reaction can be carried out in a variety of non-reactive solvents such as acetone, tetrahydrofuran, tertiary amides such as Ν, Ν-dimethylformamide and chlorinated hydrocarbons such as dichloromethane, dichloroethane, and chloroform. The reaction medium may also contain a base as an acid binding agent. Examples of suitable bases for use herein are pyridine, trimethylamine, N-methylmorpholine, sodium hydrogen carbonate and sodium hydride. A preferred solvent is acetone containing triethylamine 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 achieve 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 crystallized.

Reaction of the tautomeric benzimidazole derivative and the sulfonyl chlorides usually results in a mixture of 5- and 6-substituted sulfonylbenzimidazole, the isomer ratio usually being 1: 1. Isomers can be separated by fractional crystallization or by column chromatography. First, the 6-isomer usually crystallizes. For example, when 2-amino-5-benzimidazolecarboxylate is reacted with dlmethylsulfamoyl chloride in acetone containing triethylamine, ethyl 1-dimethylamino-sulfonyl-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 sulfonylbenzimidazole precursor. When the reaction is carried out on a precursor which is an isomeric mixture of sulfonylbenzimidazoles, the isomeric products may be separated by fractional crystallization or chromatography.

It will be appreciated that the individual chemical processes may advantageously be 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.

Sulfonylbenzimidazole compounds wherein R 2 is a heterocyclic group, for example tetrazole, can be obtained as follows. In general, the 5 (6) - (1-alkylthetrazol-5-yl) sulfonylbenzimidazole derivatives of formula (I) and 2-substituted 5 (6 '- (1-alkylthetrazol-5-yl) benzimidazole derivatives can be prepared as follows. The 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 202560 iodide in acetone and triethylamine to give 1- (2) -methyl-5- (3-nitro-4-acetamidophenyl) tetrazole as a mixture of isomers. 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 nitro group of the benzene core 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.

The diaminophenyltetrazole is reacted with cyanogen bromide in a mixture of methanol and water to give the substantially single methylated isomer, 2-amino-5 (6) - (1-methyltetrazol-5-yl) benzimidazole.

This benzimidazole is reacted with dimethylsulfamoyl chloride in acetone in the presence of triethylamine, the product being 1-dimethylaminosulfonyl-2-amino-5 (6) - (1-tetrazol-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, an additional 5 (6) - (1-alkylthetrazol-5-yl) sulfide can be obtained the 1-benzimidazole derivatives of the general formula 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 Heterocyclic Compounds, Imidazole and Its Derivatives, Interscience Publishers Co., New York, 1953.

2-Aminobenzimidazole derivatives can be obtained by cyclization of the corresponding o-phenylenediamine with cyanogen bromide as described by Buttle et al., Bio. J. 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, benzesulfonyl chloride and 2-thiophenesulfonyl chloride are commonly supplied. Further alkylsulfonyl chlorides having from 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-Dialkylsulfamoyl chlorides can 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

Ri-Cl with sulfur dioxide at a temperature of -5 ° C. The chloramine derivatives are obtained by reacting the corresponding secondary amine with antimony chloride, sodium hypochlorite or sulfuryl chloride.

Further examples of sulfonyl chlorides which can be used to react with benzimidazole compounds are ethyl, propyl, 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-Ν-isopropyl-, N-ethyl N-isopropyl- , N-propyl-N-isopropyl and diisopropylsulfamoyl chlorides.

For uniformity of nomenclature, sulfonylbenzimidazoles will be referred to as 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 and R 1 is hydrogen.

The following examples describe the practice of the process of the invention, and the products of formula I. The term "m / e" used to characterize the product means 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.

Example 1

Also 5- (3-nitro-4-acetamidophenyl) tetrazole

A solution of 10.3 g (0.05 mol) of 3-nitro-4-acetamidobenzonitrile, 3.5 g of sodium azides and 3.9 g of ammonium chloride and 100 ml of dimethylformamide was heated to reflux for 16 hours. After cooling, the reaction mixture was poured into 50 ml of 1N hydrochloric acid and diluted with 300 ml of water. The yellow product which precipitates was collected by filtration to give 5- (3-nitro-4-acetamidophenyl) tetrazole (10 g, 81% yield), mp 210-213 ° C with decomposition.

B) 1- (2'-Methyl-5- (3-nitro-4-acetamidophenyl) tetrazole)

31.7 g (0.13 mol) of 5- (3-nitro-4-acetamidophenyl) tetrazole are dissolved in 200 ml of acetone. 23 ml (0.17 mol) of triethylamine are added to the reaction mixture, which is stirred until homogeneous, and 30 ml of methyl iodide are added, followed by 20 ml of methyl iodide after standing at room temperature for 12 hours. The reaction is allowed to proceed for a further 4 hours, the precipitated product is collected by filtration and the filtrate is concentrated to its original volume in vacuo. The product was obtained in a cell of 202560 with an amount of 20 g of metal and in a yield of 59% as a mixture of isomers of 1- (2) -methyl-5- (3-nitro-4-acetamidophenyl) tetrazole.

For C 10 H 10 N 6 O 5 (162) calculated: 45.80% C, 3.84% H, 32.05% N; Found: 45.64% C, 3.84% H, 32.18% N.

C) 1- (2) -methyl-5- (3-nitro-4-aminophenyltetrazole gl (2) -methyl-5- (3-nitro-4-acetamidophenyl) tetrazole are added to 20 ml of concentrated sulfuric acid at room temperature The tetrazole slowly dissolves with stirring for 2 hours, then poured carefully into 200 ml of cold water, and the precipitated product is collected by filtration to give 1 (2) -methyl-5 (1.6 g, 95% yield). - (3-nitro-4-amino) tetrazole, m.p. 200 ° C.

For C 6 H 6 N 6 O 2 (220) calculated: C 43.64, H 3.66, N 38.17; Found: C, 43.37; H, 3.70; N, 37.89.

D) 1- (2) -Methyl-5- (3,4-diaminophenyl) tetrazole gl (2) -methyl-5- (2-nitro-4-aminophenyl) tetrazole is hydrogenated at a pressure of 4.13 x 10 &^lt; ² > g of palladium on charcoal in 135 ml of ethyl acetate and 350 ml of absolute ethanol. After 2 hours, 3 equivalents of hydrogen are absorbed. The catalyst was filtered off and the filtrate was evaporated in vacuo to give 1 (2) -methyl-5- (3,4-diaminophenyl) tetrazole (12 g, 98%).

For C 6 H 10 N 6 (190) calculated: C 50.52, H 5.30, N 44.18; Found:% C, 50.79;% H, 5.57;% N, 43.95.

E) 1- (2) -Methyl-5- (2-aminobenzimidazol-5- (6) -yl) tetrazole

3.2 g (0.03 mol) of cyanogen bromide are added to a suspension of 5.7 g (0.03 mol) of 1 (2) -methyl-5- (3,4-diaminophenyl) tetrazole in 300 ml of water and 30 ml of methanol . The mixture was stirred for 12 hours, then filtered and the filtrate was neutralized with potassium carbonate. The precipitated product was collected, yielding 5.7 g and 88% yield of 1 (2) -methyl-5- (2-aminobenzimidazol-5 (6) -yl) tetrazole.

For C 9 H 9 N 7 (215) calculated: 50.23% C, 4.22% H, 45.56% N; found: 49.56 ° C, 4.34% H, 44.06% N.

F) 1-dimethylaminosulfonyl-2-amino-5 (6) - (1 (2) -methyltetrazol-5-yl) benzimidazole

2.2 g (0.01 mol) of 1- (2) -methyl-5- [2-aminobenzimidazol-5 (6) -yl) tetrazole, 50 ml of acetone, 1.5 ml of triethylamine and 1 g of dimethylsulfamoyl chloride are heated to reflux for 18 hours. After cooling, unreacted starting material was collected by filtration and the filtrate was evaporated in vacuo to a red oily residue which was triturated with methanol to give 300 mg of 1-dimethylaminosulfonyl-2-amino-5 (6) - (1 (2) - methyltetrazol-5-yl] benzimidazole.

For C 11 H 14 N 8 O 2 S (322) calculated: 40.99% C, H 4.38%, N 34.76%; Found: C, 40.72; H, 4.38; N, 34.51

A) 1-isopropyl-5- (3-nitro-4-aminophenyl) tetrazole, m.p. 126-128 ° C, yield 71%

For C 10 H 12 N 6 O 2 (200) calculated: 48.38% C, 4.87% H, 33.85% N; Found:% C, 48.19;% H, 4.93;% N, 33.61.

B) 1-Isopropyl-5- (3,4-diaminophenyl) tetrazole in 70% yield

For C 10 H 11 N 6 (218) calculated: 55.03% C, 6.47% H, 38.50% N; Found: C 55.23, H 6.27, N 38.73.

C) 1-Isopropyl-5- [2-aminobenzimidazol-5 (6) -yl] -tetrazole, m.p. 232-233 ° C, yield 7.3 g (86%).

For C11H13N7 (243) calculated: 54.31% C, H 5.30, N 40.30; Found:% C, 54.56;% H, 5.54;% N, 40.53.

D) 1-dimethylaminosulfonyl-2-amino-5 (6) - (1-isopropyltetrazol-5-yl) benzimidazole, m.p. 211-213 ° C.

For C 13 H 18 N 8 O 2 S (350) calculated: 44.56% C, 5.18% H, 31.98% N;

Found: C 44.83, H 5.33, N. 31.77.

The compounds of formula I have a broad spectrum of antiviral activity. They are particularly effective in inhibiting the growth of echo, Mengo,

Coxsackie (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, Massachussetts 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) are grown in 25 ml Falcon flasks at 37 ° C in 199 and 5% inactivated fetal bovine serum (FBS) supplemented with penicillin in amounts. 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, Coxsackie, 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 of 1% Ionagar No. 2 and 1 part of twice concentrated medium 199 with FBS, penicillin and sterptomycin 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. 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 (Madin-Darby canine kidney cells).

Plaques were 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 to fix the cell layer to the fabric surface. The plaques formed by the virus, regardless of their size, were counted after staining the surrounding areas with crystal violet. The number of plaques was compared to the number of plaques in the control bottle for each drug concentration. The efficacy of the test substance was expressed as a percentage reduction in plaque count. That is, the concentration of the active ingredient Iso is 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 formula (I) has also been demonstrated for other virus cultures, for example Coxsackie (A9, A21, B5), echovirus (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 the formula I are summarized in Table I. The first column shows the example number, the second column the isomer type, columns 3 to 10 show the plaque reduction at different drug dilutions ranging from 0.75 to 100 micrograms. mh χ

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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)

A process for the preparation of 1-sulfonylbenzimidazoles substituted on a carbonyl group of the formula I SCkR (I) wherein R is C 1 -C 4 alkyl or the group -NR 3 R 4 in which R 3 and R 4 are the same or different denotes alkyl and 1 to 3 carbon atoms, R 2 is 1- (alkyl) tetrazol-5-yl of 1 to 3 carbon atoms in the alkyl moiety, at the 5 or 6 position, characterized in that a compound of formula II of the invention is reacted wherein: R2 is C1-C3 alkylthetrazol-5-yl with the sulfonyl chloride of formula III RSO2CI (III) where R is as defined above, in the presence of an organic solvent at room temperature to reflux.