CS202561B2 - 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 Bynoc, Lancet 1, 16, 1966) show that 74% of those with upper respiratory tract infection were infected with rhinoviruses. As more than 80 strains of rhinoviruses are known, vaccination is almost impracticable, 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 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 carbonyl-substituted 1-sulfonylbenzimidazoles of Formula I

where

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

R2 is 1,3-dithiolan-2-yl or 1,3-dithian-2-yl, in the 5 or 16 position, characterized in that the compound of formula II is reacted

(II) where

R is as defined above, with ethanedithiol or 1,3-propanedithiol in the presence of an organic solvent at room temperature.

The term "tautomeric benzimidazoil" refers to benzimidazole, which may be substituted on any nitrogen atom by hydrogen. 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 (6j-substituted benzimiidazole with the sulfonyl chloride of formula III) results in an isomeric mixture of 5 (6) -substituted sulfonylbenzimidazoles.

The term "1,3-dithiolan-2-yl" refers to

The 1,3-dithiolane bound at the 2-position. The term "1,3-dithithlan-2-yl" refers to a 1,3-dithiolane residue bound at the 2-position.

The term "alkyl of 1 to 4 carbon atoms" refers to the aliphatic radicals of 1-4 carbon atoms, straight or branched chain and ¹ to, 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 starting reagents are benzimidazole derivatives with 5 (6) -substituents which do not react with the sulfonyl chloride under the reaction conditions The benzimidazole derivatives and the sulfonyl chloride are generally used in approximately equimolar amounts, although a small excess of either may be used. in a wide 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. is pyridine, triethylamine, N-methylmorpholine, sodium bicarbonate and sodium hydride, and the 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 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 sulfonylbenzimidazole derivative solution is concentrated to crystallize 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 ratio of isomers being usually 1: 1. The isomers may 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 dimethylsulfonyl chloride in triethylamine-containing acetone, ethyl 1-dimethylaminosulfonyl-2-amino-6-benzimidazolecarboxylate crystallizes first from the reaction mixture. The acetone solution then contains predominantly the ethyl 1-dimethylaminosulfonyl-2-amino-5-benzimibenzimidazole derivative is concentrated to a 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 be advantageously performed at some stage in the synthesis of the resulting materials. The benzoimidazole 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. Particularly suitable benzimidazole reactants are 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-benzylimidazolecarboxylic acid ethyl ester) since the ester function can be used to produce other intermediates which can then easily be converted to the final products.

Ethyl esters of 1-sulfonyl-2-substituted-5- (6'-benzimidazolecarboxylic acids) can be chemically reduced to give the corresponding hydroxymethyl intermediates, for example ethyl-1-dimethylaminosulfonyl-2-acetamido-5 (6) 202561

-benzimidazolecarboxylate sodium bis- (2-methoxyethoxy) aluminum hydride in tetrahydrofuran to give 1-dimethylaminosulfonyl-2-acetamido-5 (6) -hydroxymethylbenzimidazole A more preferred procedure is to react the sulfonyl chloride RSO 2 Cl with the corresponding substituted 2-5 (6'-hydroxymethylbenzimidazole). 5 (6) -Hydroxymethylbenzimidazole can be obtained from the corresponding ethyl-2-substituted-5 (6) benzimidazolecarboxylic acid by reduction of sodium bis- (2-methoxyethoxy) aluminum hydride in an aprotic solvent as described above. The benzyl alcohol is reacted with ammonia to form 4-amino-3-nitrobenzyl alcohol and the nitroalcohol is catalytically hydrogenated to form 4-hydroxymethyl-o-phenylenediamine. The phenylenediamine is ring-closed to give the desired 2-substituted-3-nitrobenzyl alcohol. 5 (6) -Hydroxymethylbenzimidazolo intermediate in a known manner.

Usually, the 5 (6'-hydroxymethylsulfonylbenzimidazole derivatives can be converted to the corresponding 5 (6) -formyl derivatives.) The oxidation of the hydroxymethylcarbinol function to give the carboixaldehyde derivative with virus inhibitory properties is completely unexpected. conversion of the carboxaldehyde function to form a double bond between the carbon and nitrogen atoms.

Sulfonylbenzimidazololecarboxaldehydes can be prepared from the corresponding 1-sulfonyl-2-substituted-5 (6'-hydroxymethylbenzlimidazole by oxidation of the hydroxymethyl group with Jones reagent, i.e. a solution of chromic and sulfuric acid in water, for example using 1-dimethylaminosulfonyl-2-amino-5 (6). 1-dimethylaminosulfonyl-2-amino-5 (6) -formylbenzimidazole, 5 (6- (1,3-Dithiol-an-2-yl)) and 5 (6) - hydroxymethylbenzimidazole are obtained by oxidation with Jones reagent. (1,3-dithian-2-yl) derivatives can be obtained by reacting 5 (6) -formylsulfonylbenzimidazole and 1,2-ethanedithiol or 1,3-propanedithiol in the presence of boron trifluoroetherate followed by isolation of the cyclic thioacetal These reactions of the carbonyl group are shown in Reaction Scheme I.

Reaction Scheme I

COOEt reduction

SO ^ R *

oxidation h _from n $ O _o RI

Αλ

W

CHO

Ψ SO ^ R

H _Z N

AA m = 2 or 3

The 5 (6) -Ketosulfonylbenzimidazole compounds in which Z is an oxygen atom can be prepared from the corresponding 5 (6j-ketobenzimidazoles by reaction with sulfonyl chloride RSO 2 Cl) These benzimidazoles can be prepared from the corresponding keto-o-phenylenediamine in a known manner. . ^9! 3791 discloses the preparation of keto o-phenylenediamines of the general formula

where

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

The process consists in ammonolysis and reduction of the 4-halo-3-nitrophenyl ketone prepared by the Friedel-Crafts reaction 1.

4-halo-3-nitrobenzoyl chloride with the appropriate hydrocarbon; or 2. halobenzene with the appropriate acid chloride followed by aromatic nitration. Ketobenzimidazoles can also be prepared from acetanilide by Friedel-Crafts acylation with an appropriate C 2 -C 8 alkanoic acid derivative. The resulting 4-keto-acetanilide is nitrated 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 undergoes ring closure to form a 2-substituted ¹ vaného 5 (6 J-ketobenimidazolu. Ketocarbonyl function but is less reactive than carboxaldehyde function. Ketofunkci can activate by protonation sulfonylbenzimidazolové compounds for acidic conditions so that a double bond between the carbon and nitrogen atoms can be easily formed.

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 Derivaties, 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. Chrne. 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) is commonly supplied. 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

R3R4N-iCl 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.

Other examples of sulfonyl chlorides that can be used to react with benzimidazole include ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, and tert-butylsulfonyl chloride.

Other useful sulfamoyl chlorides are diethyl-, dipropyl-, N-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 called sulfonyl derivatives. For example, the product of the reaction between dimethylsulfamoyl chloride and 2-amino-5-benzylbenzimidazole is called 1-dimethylaminosulfonyl-2-amino-5 (6) -benzoylbenzimidazole and not 1-dimethylsulfatmoyl-2-anino-5 (6) -benzoylbenzimidazole.

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

Examples of derivatives of formula I include the following:

1-isopropausulfonyl-2-amino-5 (6) - (1,3-dithian-2-yl) henzimidazole and 1-dimethylanunosulfonyl-2-ainino-5 (6) - (1,4-dithiolan-2-yl) ) benzimidazole.

The following examples describe the practice of the process of the invention, 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

268 mg (1 mmol) of 1-dimethylaminosulfonyl-2-amino-5 (6) -phenylmethylbenzimidazole, 5 ml of methanol, 0.2 ml of ethanedithiol and 0.2 ml of boron trifluoride etherate are reacted at room temperature for 2 hours. . the precipitated product was filtered off, prctmyje with cold methanol, "to give 65 mg of the cyclic thioacetal, 1-onyl dime.thylaminosulf 2-amino-5 ^J '(J 6 - (dithiolane-2-yl) benzimidazole. the methanol used for The aqueous solution was extracted with ethyl acetate, the extract was washed with a saturated sodium chloride solution and dried with magnesium sulfate, the ethyl acetate was evaporated to dryness in vacuo, the residue was mixed with methanol, the insoluble material was evaporated. The solids were collected to give 155 mg of 1-dimethylaminosulfonyl-2-amino-5 (6 µl of 1,3-dithiolan-2-yl) -benzimidazole. The methanol filtrate was evaporated to dryness in vacuo to give more than 95 mg of product.

m / e = 344.

Example 2

22.0 mg (0.8 mmol) of 1-dimethylaminosulfonyl-2-amino-1 H -bj-formylbenzimidazole, 2 mL of methanol, 0.15 mL (1.6 mmol) of 1,3-propanedithiol and 0.75 mL of boron trifluoride in the etherate is shown at room temperature. 6 ml of ether was added to the reaction mixture and the reaction was allowed to proceed for 2 hours. The reaction mixture was diluted to 12 mL with ether and the product precipitated. The mixture is centrifuged and the supernatant is decanted. The precipitate is suspended in ether and the mixture is centrifuged again. The supernatant was decanted and the solid product was dried under vacuum to give 1-dimethylaminosulfonyl-2-amino-5 (6) - (1,3-diethan-2-yl) cyclic thioacetal in 224 mg and 75% yield. benzimidazole. m / e = 358.

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 (225 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 the 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) The specific assays will be described in detail below.

Experimental methods

Monkey kidney cells (BSC-1) or Helabush cells (5-3) are grown in 25 ml Falcon bottles at 37 ° C in 199 and 5% inactivated Fetal Serum Serum (FBS), with penicillin addition. 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 1% Ionagar

No. 2 and 1 part of twice-concentrated medium 199 with the addition of FBS, penicillin and streptomycin and containing the active substance in concentrations of 100, 50, 25, 12, 6, 3 and 0 microorganisms in ml. A bottle that does not contain the active substance is a control. Stock solutions of compounds or thiazolinbenzimidazolových thiazinylbenzimidazolových compounds of formula I are prepared in DMSO at a concentration of 10 ⁴ .mikrogramy / mi. 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 (type A, B) were incubated for 72 hours at 37 ° C using MDCK cells (Madin-Darby dog 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 bottle 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 plaques was compared to the number of plaques in the control bottle for each drug concentration. Efficacy 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 10 micrograms. ml.

Table I

Reduction of polio virus plaques with 1-substituted sulfonyl-2-amino-5 (6) -substituted benzimidazoles

Concentration of active substance in milk programs / ml

Example. Isomer 10-0. 5) 0 25 12 6 3 1.5 0.75 1 3 (6) 100 ALIGN! 100 ALIGN! 100 ALIGN! 100 ALIGN! 100 ALIGN! 99 54 27 Mar: 1 6 100 ALIGN! 100 ' 100- 100 ALIGN! 100 ALIGN! 100 ALIGN! 76 41 2 5 (6) 100 ALIGN! 100 ALIGN! 100 ' 100 ALIGN! 98 68 15 Dec O

The 1-thiazolimylbenzimidazole 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, for the decontamination of surfaces in which poliovirus, Coxisackie virus, rhinovirus or influenza virus is present, including glass used in non-hospitals, of all ophthalmic surfaces. and especially the environment used to prepare the food.

The compounds of the 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 repeated periodically in case of need. 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 depending on 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 initranasal sprays.

Claims (1)

SUBJECT A process for the preparation of 1-sulfonylbenzimidazoles substituted on the carbonyl group of the general formula (I) Í / Z where R is C 1 -C 4 alkyl or -NR 3 R 4 in which R 3 is C 1 -C 4 alkyl; R3 and R4 identical or different denote alkyl having 1 to 3 carbon atoms, YNÁLEZU R2 is 1,3-dithiolan-2-yl or 1,3-dithian-2-yl, in the 5 or 6 position, characterized in that a compound of formula II is reacted in the reaction wherein: R is as defined above, with ethanedithiol or 1,3-propanedithiol in the presence of an organic solvent at room temperature.