PL110143B1 - Method of producing new carbonyl substituted 1-sulfonylobenzimidazoles - Google Patents

Description

The present invention relates to a process for the preparation of new, carbonyl-substituted 1-sulfonylbenzimidazoles of the general formula I, in which: R represents a -alkyl group containing 1-4 carbon atoms or a group of the formula -NR3R4J in which R3 and R * independently represent alkyl groups containing 1 - 3 carbon atoms, Rt is hydrogen, R2 is hydrogen, alkyl group containing 1-4 carbon atoms or phenyl group, Z is alkoxyimino group, in which alkoxy group contains 1-4 carbon atoms or benzyloxyimino group, substituted The factor of formula 3 is in the position 5 or 6, and n is the number 1. These compounds inhibit the growth of viruses, especially rhinoviruses, poliomyelitis viruses, and Coxsackie, ECHO and Mengo viruses, and they have more favorable properties than the known compounds with Virus-induced upper respiratory tract disease is vast. It has been found that in the United States alone, there are one billion cases of the disease each year. Research conducted in England (Tyrell and Bynoe, Lancet 76 (1966)) showed that 74% of people suffering from influenza were infected with rhinoviruses. As far as it has been established, the virus has at least 80 variants, making the development of an effective a vaccine is not possible and therefore the use of chemotherapy may have the desired effect. The usefulness of chemicals to inhibit the growth of viruses "in vitrio" can easily be ascertained in the viral plaque suppression test, similarly as described by Siminoff (Applied Microbiology, 9 (1), 66, 1961). Some 1- (N, N-dimethylanino sulfonyl) -2-aminobenzimidazoles with antifungal properties are described in U.S. Patent No. 3,853,908. Process for the preparation of novel carbonyl-substituted sulfonylbenzimidazoles of general formula I in which all the symbols have the above meaning, according to the invention, consists in that the compound of the general formula 2, wherein R2 and n have the above meaning, It is reacted with a sulfonyl chloride of formula RSO 2 Cl, wherein R is as defined above, to give an intermediate of formula I, wherein R t is hydrogen, Z is oxygen, and n, R and R2 are as defined above. The resulting compound is then reacted with hydroxylamine, 1-4 carbon alkoxyamine or benzyloxyamine to give a compound of formula I wherein Z is an alkoxyimino group of 1-4 carbon atoms or a benzyloxyimine, or a transient compound of formula I wherein Z is the group hydroxyimine which is alkylated to give the compound of formula I wherein Z is an alkoxyimino group of 1-4 carbon atoms or a benzyloxyimino group. The term "tautomeric benzimidazole" denotes benzimidazole which may contain a hydrogen atom on any nitrogen atom. Benzimidazole unsubstituted on nitrogen and containing a substituent in the 5-position of the benzene portion has a tautomeric variation in which the substituent is in the 6-position. An isomeric mixture can be determined by giving alternative positional values, including 110 143 110 143 3 in case 5 (6). tautomerism, by reacting a 5-substituted benzimidazole (6) with a sulfonyl chloride of formula RSO 2 Cl, gives isomeric mixture of sulfonylbenzimidazoles substituted in position 5 (6). The following terms and definitions are used in this specification. The term "alkyl group having 1-4 carbon atoms" denotes straight or branched aliphatic hydrocarbon radicals such as methyl, ethyl, isopropyl groups , butyl, isobutyl, T-butyl and T-butyl. This term includes, different from the term "alkyl groups containing 1-3 carbon atoms" -pkrMtme - "alffoxyl group containing 1-4 wig atoms" - tthia, which corresponds to the phytochemicals of aliphatic ethers with straight or branched chains containing 1-4 atoms carbon, such as methoxy, ethoxy, prbppxyly, isopropoxy, butoxy, isobutoxy # Hl ^ rz "." Buffggsyl ". The term" alkylamino group having 1-4 carbon atoms "means aliphatic amine radicals with 1-4 carbon atoms methylamine, ethylamine, propylamine, isopropylamine, butylamine and II-butylamine. The term "alkoxyamino group having 1-4 carbon atoms" means an O-aliphatic hydroxylamine radical with 1-4 carbon atoms derived from hydroxylamine Methoxyamine hydrochloride is commercially available. Other hydroxylamine derivatives may be obtained by: (A) alkylation of acetone oxime with 1-4 atoms alkylchlorides and acid hydrolysis, (B) alkylation of N-hydroxyphthalic of the imide and then hydrazinolize or (C) alkylation of benzohydroxamic acid and acid hydrolysis. Preferred substrates are benzimidazole derivatives bearing substituents at position 5 (6) which do not react with sulfonyl chloride under the reaction conditions. These reagents are used in approximately equimolar amounts, although an excess of one may be used if desired. The reactions are carried out in any solvent inert to the reaction, such as acetone, tetrahydrofuran (THF), tertiary amides, such as, for example, N, N-dimetic) formamide (DMF), and chlorinated hydrocarbons, such as, for example, dichloromethane, chloroform dichloroethanes. it may also contain a base which serves to bind the acid formed during the reaction. Suitable bases for this purpose are pyridine, triethylamine, N-merylmorpholine, acidic sodium carbonate and sodium hydride. The reaction takes place preferably in a medium of acetone and triethylamine or in a mixture of tetrahydrofuran and N, N-dimethylformamide with the addition of a hydride base. The reaction is most preferably between room temperature and the boiling point of the solvent system used. It is preferable to carry out the reaction at reflux temperature in which the reaction takes place completely for 1-48 hours. The reaction product is 1-sulfonylbenzimidazole, hereinafter referred to as sulfonylbenzimidazole. It can be isolated from the reaction mixture by filtering and concentrating the filtrate to the concentration in which the product crystallizes. Otherwise, the reaction mixture is evaporated to dryness and the residue is treated with acetone or methanol 4 to separate and remove the insolubles. The solution containing the sulfonyl benzimidazole is concentrated to crystallize the product or evaporated to give a second residue which dissolves into. For example, in methanol, the sulfonylbenzimidazole is separated by crystallization. The reaction of the tautomeric benzimidazole with sulfonyl chloride normally produces a mixture of 5 or 6 substituted sulfonyl benzimidazole isomers in a 1: 1 ratio. Isomers are separated by column chromatography or by fractional crystallization. Typically, from a solution containing a mixture of isomers, the isomer first crystallizes with the substituent at position 6. 15 The isomers can be identified by comparing the nuclear resonance magnetic spectra of phenyl protons ranging from 7.0 to 8.3 ppm. When the isomeric mixture is reacted, Nine sulfonyl benzimidazoles, the resulting isomers can be separated by fractionated crystallization or by chromatography. The sulfonyl benzimidazole intermediate is further reacted to yield the end product. Benzimidazoles containing groups that can be converted to the given 25 substituents (6) by reaction with the appropriate sulfonyl chloride are suitable. Benzimidazole-5 (6) ethyl esters substituted in the 2-position are particularly suitable substrates since the ester function readily reacts to form other intermediates that can be converted to end products. An example of an intermediate of formula I wherein Z is oxygen is a 5 (6) -formyl derivative having viral inhibitory activity. Further transformation of the aldehyde group into a group containing a double bond between carbon and nitrogen atoms increases the antiviral activity of such a compound to a large extent. The formyl derivative of sulfonylbenzimidazole can be converted into a 5 (6) -benzyloxyiminomethylene derivative, in which a 5 (6) alkoxinomethylene derivative is the alkoxy group contains 1-4 carbon atoms or an intermediate hydroxyiminomethylene derivative by reaction with benzyloxyamine, with alkoxyamines having 1-4 carbon atoms in the alkoxy group, or with hydroxyamine. The reactions were carried out in the usual manner due to the high reactivity of the aldehyde group. The above-mentioned reactions of the carbonyl group are presented in the attached diagram, where in the formulas in the scheme R5 represents the OH group, a group of the formula 0-alkyl with 1-4 carbon atoms or of the formula OCH3C6H5. Intermediate sulfonyl-5 (6) -ketobenzimidazoles, wherein Z is oxygen is obtained by reacting the corresponding 5 (6) -ketobenzimidazoles with a sulfonyl chloride of formula RSO 2 Cl. The starting ketobenzimidazole can be obtained by known methods used in the synthesis of benzimidazoles from the corresponding keto-o-phenylenediamine. The published description of the Belgian patent application No. 93 791 describes the preparation of keto-o-phenylenediamines of formula 4, in which R2 is the lower an alkyl, cycloalkyl or phenyl group optionally substituted by halogen, a lower alkyl group or a lower alkoxy group. This process uses ammonolysis and reductions of 4-chloro-3-nitrophenyl ketone, which is obtained by Friedel-Crafts reaction in one of two ways: 1) by reacting 4-halo-3-nitrobenaoyl chloride with the appropriate hydrocarbon, or 2) by reacting • halobenzene with the appropriate acid chloride and then nitrating the aromatic ring. Optionally, ketobenzimidazoles are prepared from acetanilide by Friedel-Crafts acylation with an alkane carboxylic acid derivative of 2 to 8 carbon atoms. The resulting 4-ketoacetanilide is nitrated to give 2-nitro-4-ketoacetanilide. Hydrolysis then yields 2-nitro-4-ketoaniline, which is converted to 4-keto-o-phenylenediamine upon catalytic hydrogenation. The latter compound is converted to the corresponding 5 (6) -ketobenzimidazole substituted in the 2-position by cyclization. The following example illustrates the preparation of sulfonyl-5 (6) -ketobenzimidazole intermediate. 4-propionylacetanilide is nitrated at 0 ° C to give 2-nitro-4-propionylacetanilide. The acetanilide is hydrolyzed and catalytically hydrogenated to give 4-propionyl-o-phenylenediamine. Phenylenediamine is reacted with cyanogen bromide to give 2-amino-5 (6) -propionylbenzimidazole. Propionylbenzimidazole is reacted with dimethylsulfamyl chloride to produce 1- (N, N-dimethylammcsulfonyl) -2-amino-5 (6) -propionylbenzimidazole. Similar to the formyl sulfonylbenzimidazole derivative sulfonyl-5 (6) -ketobene Zimidazole can be reacted with hydroxyamine with 1-4 carbon alkoxyamines to give derivatives of 1-4 carbon alkoxyamines or other derivatives. However, the carbonyl ketone group is less reactive than the aldehyde group. The ketone group can be activated by protonation of sulfonylbenzimidazole in an acidic environment, resulting in easier formation of the double bond between the carbon and nitrogen atom. The functional groups containing the nitrogen atom are named accordingly to the carbonyl reagent. for example: carbonyl reagent methoxyamine ethoxyamine propoxyamine butoxyamine ¦benzyloxyamine name of the group containing) nitrogen atom methoxyimino group ethoxyimino group butoxyimine group benzyloxyimine group Benzimidazoles used as substrates in the above process can be obtained by various methods known in the art. The Chemistry of Heterocyclic Compounds. "(A. Weissberger Ed.), Part 1 -" Imidazole and Its Derivatives ", Interscience Publishers Co., N. York, 1953." Initial 2-aminobenzimidazoles can be obtained by cyclization of of the corresponding o-phenylenediamines using cyanogen bromide as described in Bio.Chem. J., 32, 1101 (1938) by Buttle et al. and in British Patent Specification No. 551,524. For commercially available sulfonyl chlorides used as reagents includes: methanesulfonyl chloride (mesyl chloride), isopropylsulfonyl chloride and dimethylsulfamyl chloride. Other alkylsulfonyl chlorides with 1 to 4 carbon atoms can be obtained by chlorination of appropriate alkyl polyols or by reaction of sulfuryl chloride with alkylated sodium sulfonates obtained from appropriate aliphatic and alcoholic acid alcohols. N, N-dialkylsulfamyl chlorides can be prepared by the method described by Bindelg et al. In J. Am. Chem. Soc., 61, 3230 (1939) by reacting the salts of secondary amines with sulfuryl chloride. They can also be obtained by reacting a chloramine of formula R3R4N-C1 with sulfur dioxide at a temperature of -5 ° C to 30 ° C. Chloramine is obtained by reacting the corresponding secondary amines with antimony pentachloride, sodium hypochlorite or sulfuryl chloride. Sulfonyl chlorides which can be used in the reaction with benzimidazoles also include ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, isylsulfonyl, isylsulfonyl, isylsulfonylchlorides, -butylsulfonyl and tert-butylsulfonyl. Among the other sulfamyl chlorides used, the following should be mentioned: N, N-diethylsulfamyl, N, N-di-propylsulfamyl, N-methyl-N-ethylsulfamyl, N-methyl- N-propylsulfamyl, N-ethyl -N-propylsulfamyl, N-methyl -N-isopropylsulfamyl, N-ethyl -N-isopropylsulfamyl, N-propyl-N-isopropylsulfamyl 25 and N, N-diisopropylsulfamyl, In order to be consistent nomenclature, Bulfonylbemdmidftzoles will be referred to as sulfonyl derivatives. For example, the reaction product of dimethylsulfamyl chloride and 2-amino-5-benzoyl-benzimidazole is called 1- (N, N-dimethylaminosulfonyl) -2-amino-5 ( 6) - benzoylbenzimidazole and not 1-dimethylsulfamyl-2-amino-5 (6) -benzoylbenzimidazole. Among the compounds of formula 1, sulfonylbenzimidazoles are preferred, in which R is isopropyl or dimethylamino, RL is hydrogen, R2 is phenyl, hydrogen or a propyl group, n is 1 and Z is alkoxyimino. in which the alkoxy group contains 1-4 carbon atoms. Examples of these compounds are 1- (N, N-dimethylaminosulfonyl) -2-amino -5 (6) - - (a-methyloxyiminobenzyl) benzimidazole. An example of derivative 5 (6) - formylsulfonylbenzimidazole of formula 1 is: 1- (N, N-dimethylaminosulfonyl) -2-amino -5 (6) - (methoxyimmomethyl) benzimidazole. An example of a 5 (8) -ketosulfonylbenzimidazole derivative of formula 1 is: 1 - (NN-dimethylaminosulfonyl) -2-amino -5 (6) - - (1-ethoxyiminobutyl) benzimidazole. The compounds of the formula I exhibit broad-spectrum antiviral activity. Their particular effectiveness consists not only in inhibiting the growth of viruses such as ECHO, Mengo, Coxsackie viruses (A9, 21, B5), poliomyelitis (types I, II, III) or 55 rhinoviruses (25 varieties), but also in inhibiting the development of various types of flu viruses, including varieties such as Ann Arbor. Maryland B, Massachusetts B, Hong Kong A, Pr-8a and TaylorC (types A and B). The ability of compounds covered by Formula 1 to inhibit the development of viruses "in vitro" is readily ascertained by attempting to suppress viral plaque growth, similar to this Described by Siminoff (Applied Microbiology 9 (1), 66, 1961) Relevant assays are described in detail below Compounds of Formula 1 were tested using the following methods: 110 143 Verve kidney cells (BSC-1) or Hela cells (5-3) were cultured. in 25 ml Falcon flasks at 37 ° C in 199 medium with 5% inactivated Fetal Bovine Serum (PBS), 150 units / l ml penicillin and 150 micrograms / ml streptomycin. After attaching the homogeneous layer, the liquid culture medium was removed and 0.3 ml of suitably diluted virus (ECHO, Mengo, Coxsackie, poliomyelitis or rhinovirus type) was added to each flask. After absorption for 1 hour at room temperature, the surfaces virus-infected cells were coated with a medium consisting of 1 part 1% Ionagar Number 2 and 1 part dual concentration medium 199 containing FBS, penicillin and streptomycin. The nutrient solution contained the drug at concentrations: 100, 50, 25, 12, 6, 3 and 0 micrograms (milliliter // flask containing no drug was considered a comparative test in the study. Stock solutions of sulfonyl benzimidazoles were prepared using a dilution with dimethyl sulfoxide to a concentration of 104 micrograms / ml. Flasks were incubated at 37 ° C for 72 hours for poliomyelitis, Coxsackie, ECHO, and Mengo viruses, and for 120 hours at 32 ° C for rhinoviruses. Lysinks were observed in these areas. that had become infected with virus and in which the virus multiplied in cells. 8 slans were added to each flask as a percentage of the reduction in the number of plaques, or * percent inhibition. Alternatively, the drug concentration indicated by the symbol I50 was used as a measure of activity, representing 50% inhibition of formation 5 The results are presented with respect to the inhibition of the growth of the poliomyelitis type I virus, since the virus n is easy to breed and consistent test results are obtained. However, the activity of the compounds of formula I was determined such that, against other viruses such as Coxsackie (A9, A21, B5), ECHO (strains 1-4), Mengo, rhinoviruses (25 strains) and poliomyelitis (types I, II, HI). The results of the tests of various sulfonyl benzimidazole derivatives are shown in Table I. Column 15 of the first Table I gives the number of the example in which the test compound is produced, the second column gives the isomer in position 5 (6) of the corresponding benzimidazole, and in the columns the third to the tenth are the percent reduction in viral plaques at drug concentrations in the range of 0.75-100 micrograms / milliliter. As mentioned, the compounds of formula I have more favorable properties than compounds known to have antiviral activity. For comparison, Table II shows the activity of a typical compound of formula I, such as 25 l-isopropylsulfonyl-2-amino -5 (6) - (a-methoxyiminobenzyl) benzimidazole (a compound of example VII) and: activity of compounds known as compounds A, B, C. Table I Growth inhibition of poliomyelitis virus type I with 1-sulfonyl-substituted-2-amino 5 (6) -substituted-benzimidazoles Example number IX 1 x 1 x XI XII xin XIV Type of isomer 6 5/6 6 5/6 6 6 6 Drug concentration in micrograms / milliliter 100 100 100 100 Toxic Toxic Toxic 36 50 100 100 100 Moderately Toxic Toxic Slightly Toxic 17 25 100 100 100 Slightly Toxic Moderately Toxic 100 6 12 100 100 100 Slightly Toxic Moderately Toxic 100 8 6 94 99 100 100 100 100 10 3 46 64 100 95 100 88 3 1.5 15 25 97 40 100 64 0 0.75 2 0 81 0 100 43 0 * 1 N Ii • y I 5 I SS h 10% formalin solution i 2% sodium acetate solution to inactivate the virus and adhere the cell layer to the surface of the flask. Virus plaques, regardless of size, were counted after the cells were stained with crystal violet. The number of lysines in a given flask was compared with the number in a comparative flask for each drug concentration, respectively. The activity of the test compound as Compound A is D- (-) - 2- (a-hydroxybenzyl) benzimidazole hydrochloride (also called HB B). Compound B is guanidine hydrochloride. Compound C is 1-dimethyl-animosulfonyl-2-amino-5 (6) -benzimidazole acetic acid ethyl ester, known from patent No. 97785.110 143 9 10 Table II Comparative data of polymelitis virus growth inhibition type I Test compound Type Drug concentration in micrograms / milliliter 100 50 25 12 3 | 1.5 | 0.75 I 0.35 | 0.17 | 0.08 Compound from example XI toxic moderately toxic 100 100 100 95 Compound A 100 88 53 20 Compound B 100 99 Compound C 5 (6) 100 77 57 44 40 0 0 fi From the comparison of the data presented in Table II it can be seen that the new compounds have more advantageous properties than the known compounds. Sulfonylbenzimidazoles have been tested both as pure compounds and as an isomeric mixture. Both isomers inhibit viral growth, but isomer 6 is usually more active than isomer 5. Compounds of formula 1 are useful for inhibiting the growth of several viruses when added to the medium in which viruses are grown. The compounds of the formula I can be used in an aqueous solution, preferably with the addition of an surfactant, to disinfect surfaces with poliomyelitis, Coxsackie, rhinoviruses and others. Such surfaces include, but are not limited to, hospital glassware, hospital work surfaces, and similar surfaces in food preparation rooms. Human warm-blooded animals may be given the compounds orally at doses of 1 to 300 mg per kg of body weight. Administration may be repeated periodically as required. In accordance with accepted practice, the antiviral compound is administered every four to six hours. The compounds of formula I are preferably used in combination with one or more excipients, depending on the mode of administration. Thus, for oral administration, the active compound is mixed with pharmaceutical diluents and carriers such as lactose, sucrose, starch flour, cellulose, talc, magnesium stearate, magnesium oxide, calcium sulphate, powdered aka gum, gelatin, alginate. sodium, sodium benzoate and stearic acid. Such preparations may be formulated for ease of administration in the form of tablets or closed capsules. In addition, these compounds may be administered parenterally. These compounds may also be mixed with liquids and applied as nasal drops or nasal spray. The examples illustrate the preparation of the intermediates and compounds of formula 1. The term "m / e" used in characterizing the products , is the ratio of mass to ta ^ and ^ and ^ * ions in the mass spectrum. Usually the m / e values correspond to the molecular weights of the main peaks. Example I. Four grams (15.6 mmol) of 2-amino-5 (6) -acetylbenzimidazole bromide, 50 ml of acetone, 5 ml (35.6 mmol) of triethylamine and 2.3 g (16.0 mmol) of diethylsulfamyl chloride was refluxed for about 12 hours. The mixture was filtered and the filtrate was evaporated under reduced pressure to give a solid residue which was dissolved in approximately 80 ml of methanol. The methanol solution was concentrated to approximately 60 mL and cooled. For crystallization, 800 mg of 1- (N, N-dimethylaminosulfonyl) -2-amino-5 (6) -acetylbenzimidazole were obtained in the form of yellow crystals. The melting point is 206-210 ° C (with decomposition). Analytical results for: CH ^OaS - molecular weight 282 calculated: C46.80 H5.00 N 19.85 Found: C47.07, H 4.99, N 19, 65.Example II. Twenty millimoles, 4.5 g of 2-amino--5 (6) -benzoylbenzimidazole were dissolved in 30 ml of acetone and 4.0 g of triethylamine. A solution of 2.9 g (20 mmol) of dimethylsulfamyl chloride in 10 ml of acetone was added dropwise to the mixture. The mixture was heated to reflux overnight. The reaction mixture was poured into 400 ml of water. The product was extracted with chloroform. The extract was washed with water, dried (Na 2 SO 4) and evaporated under reduced pressure. The residue was crystallized from ethyl acetate to give 1.06 g of 1- (N, N-dimethylamosulfonyl) -2-amino-6-benzoyl-benzimidazole, mp 206-208 ° C. Analysis results for: C16H16N403S - molecular weight 344 was calculated : C 55.82, H4.65, N 16.28 Found: C 56.27, H4.80, N 15.95. Example III. A solution containing 0.423 g of 1- (N, N-dimethylaminosulfonyl) -2-amino-5 (6) -acetylbenzimidazole and 0.300 g of hydroxylamine hydrochloride in 60 ml of methyl alcohol was refluxed for 17 hours. hours.The solution was concentrated to half its original volume using a steam bath for heating. Then 30 ml of buffer solution (pH = 7.00) was added to the residue. A precipitate formed which was filtered off and dried, yielding 0.318 g of 1- (N-dimethylaninosulfonyl) -2-amino-5 (6) - (α-hydroxyiminoethyl) benzimidazole, mp 222-225 ° C (with decomposition). for: CnH, NsOaS, molecular weight 297, calculated: C44.43, H5.09, N 23.55, found: C44.64, H4.96, N 23.21. One hundred and seventy two milligrams of 1- (N, N-dimethylaminosulfonyl) -2-amino -5 (6) -benzoyl benzimidazole, 100 mg of hydroxylamine hydrochloride and 20 ml of methanol were refluxed for 16 hours. The mixture was concentrated to half its original volume by heating on a steam bath and 10 ml of buffer (pH 1.0) was added. The precipitate was filtered off, yielding 116 mg of 1- (N, N-dimethylaminosulfonyl) -2-amino -5 (6) - (a-hydroxyiminobenzyl) benzimidazole, mp 180-183 ° C. Analysis results for: C16H17N503S - molecular weight 359 calculated: C 53.47, H4.77, N 19.49 Found: C52.38, H5.13, N 18.58. Example 5. Solution containing 0.135 g of 1- (N, N-dimethylaminosulfonyl) ) -2-amino -5 (6) -formylbenimidazole and methoxyamine hydrochloride in 20 ml of methyl alcohol, were heated under reflux for 17 hours. The color of the solution varied from red to yellow. The reaction mixture was concentrated to half the original volume and then 9 ml of buffer solution (pH = 7.00) was added. The mixture was concentrated by evaporation, filtered, washed with water and dried. 0.042 g of -1- (N, N-dimethylaminosulfonyl) -2-amino-5 (6) - (methoxyiminomethyl) benzimidazole with a m / e value of 297 was obtained. Example VI. A solution of 0.141 g (0.0005 mol) 1- (N, N-dimethylaminosulfonyl) -2-alpha-5 (6) -acetylbenzimidazole and 0.120 g (0.00145 mol) methoxyamine hydrochloride in 20 ml methyl alcohol was kept in the boiling under reflux within 19 hours. The solution was concentrated on a steam bath to half the original volume and then an equal volume of water was added to the residue. The resulting solution was concentrated until precipitation began, and a buffer solution (pH = 7.00) was added to the residue to enhance crystallization. The solution was then filtered, the precipitate washed twice with water and dried to give 0.075 g of 1- (N, N-dimethylaminosulfonyl) -2-amino-5- (6) - (α-methoxyiminoethyl) benzimidazole, mp 183 ° -185 ° C. Analysis results for C12H17N503S - Molecular Weight 311 Calculated: C46.29, H 5.50, N 22.49 Found: C46.50, H5.43, N —22.22. Example VII. By the method described in Example 6, using 0.688 g (0.002 mol) of 1- (N, N-dimethylaminosulfonyl) -2-amino-5 (6) -benzoylbenimidazole, 0.500 g of methoxyamine hydrochloride and 80 ml of methyl alcohol as starting materials, 0.530 g was obtained 1- (N, N-dimethylaminosulfonyl) -2-amino -5 (6) - (o-methoxyimino-benzyl) -benzimidazole with a melting point of 210—213 ° C. Analysis results for: C17H19N503S - molecular weight 373 calcd: C 54.68, H5.13, N — 18.75. Found: C 54.66, H5.06, N 18.92. Example VIII. By the method of Example VI, 1.7 g of 1-isopropylsulfonyl-2-amino-5 (6) -benzimidazole, 1.2 g of methoxyamine hydrochloride and 200 ml of methyl alcohol gave an oil which was washed with saturated sodium chloride solution and it was then extracted with ethyl acetate and the extract was dried. After repeated extraction with benzene, 1 g of 1-isopropylsulfonyl -2-amino -5 (6) - (α-methoxyiminobenzyl) benzimidazole was obtained in the form of a solid foam (therefore the melting point could not be determined). 10 15 20 25 30 35 40 45 50 55 60 65 Analysis results for: C18H20N4O3S - molecular weight 372, calculated: C58.05, H5.41, N 15.04, found: C57.98, H5.72, N 14, 99.Example IX. To 15 ml of 95% ethyl alcohol, 0.718 g (0.002 mol) of 1- (N N-dimethylaminosulfonyl) -2-amino -5 (6) - (α-hydroxyiminobenzyl) benzimidazole was added with stirring. To this solution, 0.120 g (0.0022 mol) of sodium methoxide and 0.552 g (0.00354 mol) of ethyl iodide were successively added. The solution was refluxed for 2.5 hours, cooled and evaporated to half its original volume, then poured into water and the resulting mixture was extracted twice with chloroform, washed twice with saturated sodium chloride solution, dried and filtered. obtaining 0.227 g of 1- (N, N-dimethylaminosulfonyl) -2-amino-5 (6) - (a-ethoxyiminobenzyl) benzimidazole, which was isolated as a white foamed substance, and thus it was impossible to determine the melting point. for: C18H21N503S - molecular weight 387. Calculated: C 55.80, H5.46, N 18.08 Found: C56.03, H5.33, N 18.27. Example X. By the method given in example IX, using 0.718 g (0.002 mol) 1- (N, N-dimethylaminosulfonyl) -2-amino-5 (6) - (α-hydroxyiminobenzyl) benzimidazole, 15 ml methyl alcohol, 0.120 g (0.0022 mol) ) sodium methoxide and 0.600 g (0.00354 mol) of 1-iodopropane, 0.248 g of 1- (NN-dimethylaminosulfonyl) was obtained -2-amino-5 (6) - (a-propoxyiminobenzyl) - benzimidazole in the form of a white foamed substance, therefore it was impossible to determine the melting point. Analysis results for: C19H23N503S - molecular weight 401, calculated: C56.84, H5 , 77, N 17.44, found: C 56.63, H 5.54, N 17.60. Example XI. A solution containing 0.172 g (0.0005 mol) of 1- (N, N-dimethylaminosulfonyl) -2-amino-5 (6) -benzoylbenzimidazole and 0.230 g (0.00145 mol) of benzyloxyamine hydrochloride in 20 ml of methyl alcohol was kept boiling under reflux within 19.5 hours. The resulting solution was then concentrated on a steam bath to half its initial volume and then 10 ml of the buffer solution (pH 7.0) was added. The precipitate was filtered off to obtain 0.161 g of 1- (N, N-dimethylaminosulfonyl) -2-amino-5 (6) - (α-benzyloxyiminobenzyl) benzimidazole. Analysis results for: C23H23N503S - molecular weight 449 calculated: C 61, 45, H5.16, N 15.58 Found: C 61.51, H5.20, N 15.37. Patent Claims 1. Method for the preparation of new carbonyl-substituted 1-sulfonylbenzimidazoles of the general formula I, in which R is an alkyl group containing 1 1 1 carbon atoms or groups of formula —NR3R4, where Rj and R4 are independently alkyl groups containing 1-3 carbon atoms, R ± is hydrogen atom, R2 is hydrogen atom, alkyl group containing 1-4 carbon atoms or phenyl group, Z represents an alkoxyimino group in which the alkoxy group contains 1-4 carbon atoms or a benzyloxyimino group, the substituent of formula III is in the 5 or 6 position, and n is the number 1, characterized by the compound of general formula II in which R2 and n have the meaning given above, is reacted with sulfonyl chloride the general formula RS020, in which R is as defined above, to give the compound of formula 1, in which R ± is hydrogen, Z is oxygen, and n, R and R2 are as defined above, which is then reacted with the alkoxyamine 1-4 carbon atoms or benzyloxyamine. 2. Method according to claim. The process of claim 1, wherein in the preparation of 1-dimethylaminosulfonyl-2-amino--5 (6) - (a-methoxyiminobenzyl) benzimidazole, 2-amino- -5 (6) -benzoylbenzimidazole is reacted with a hydride with sodium and dimethylsulfamyl chloride and then with methoxyamine hydrochloride. 3. Process for the preparation of new carbonyl substituted 1-sulfonylbenzimidazoles of the general formula I, in which R is an alkyl group containing 1-4 carbon atoms or a group of the formula —NR3R4, in which R3 and R4 are independently alkyl groups containing 1-3 carbon atoms, R ± represents a hydrogen atom, R2 represents a hydrogen atom, an alkyl group containing 1-4 carbon atoms or a phenyl group, Z represents an alkoxyimino group in which the alkoxy group contains 1-4 carbon atoms or a benzyloxyimino group, a substituent of the formula 3 is in position 5 or 6, and n is the number 1, characterized in that the compound of general formula 2, in which R2 and n are as defined above, is reacted with a sulfonyl chloride of general formula RSO2C1 in which R is above the meaning given to give the intermediate of formula I, where Rt is hydrogen, Z is oxygen, and n, R and R2 are as defined above, which is reacted with hydroxylamine and then alkylated indirectly short Formula I wherein Z is hydroxyimino and the other symbols are as defined above to give the compound of Formula I wherein Z is an alkoxyimino group with 1-4 carbon atoms or a benzyloxyimino group. 4. The method of claiming 3. The process according to claim 3, characterized in that in the preparation of 1- (N, N-dimethylaminosulfonyl) -2-amino-5 (6) - (α-ethoxyiminobenzyl) benzimidazole, 2-amino-5 (6) -benzoylbenzimidazole is subjected to reaction with sodium hydride and dimethylsulfamyl chloride and then with hydroxylamine hydrochloride, then the obtained product is reacted with sodium methoxide and ethyl iodide. 5. The method according to p. 3. The process of claim 3, characterized in that in the preparation of 1- (N, N-dimethylaminosulfonyl) -2-amino -5 (6) - (α-propoxyiminobenzyl) benzimidazole, 2-amino-5 (6) -benzoylbenzimidazole is subjected to It is reacted with sodium hydride and dimethylsulfamyl chloride, and then with hydroxylamine hydrochloride, and the product obtained is reacted with sodium methanolate and 1-iodopropane. Formula 1 H Formula 2 M c - o ^ NH2 Formula HH »N- <S0aR XCH0 RSNH: 51 ^ 2 S0aR Rs HN ^ J ^ H Scheme PL

Claims (5)

Claims 1. A method for the preparation of new carbonyl substituted 1-sulfonylbenzimidazoles of the general formula I, in which R is an alkyl group containing 1-1 carbon atoms or a group of the formula -NR3R4, in which R1 and R4 are independently alkyl groups containing 1-3 carbon atoms , R ± is a hydrogen atom, R2 is a hydrogen atom, an alkyl group containing 1-4 carbon atoms or a phenyl group, Z is an alkoxyimino group in which the alkoxy group contains 1-4 carbon atoms or a benzyloxyimino group, the substituent of formula III is in position 5 or 6, and n is the number 1, characterized in that a compound of general formula 2, in which R2 and n have the meaning given above, is reacted with a sulfonyl chloride of general formula RS020 in which R is as defined above to give the compound of formula I, wherein R ± is hydrogen, Z is oxygen, and n, R and R2 are as defined above, which is then reacted with an alkoxyamine of 1-4 atoms ah carbon or benzyloxyamine. 10 2. The method of claiming The process of claim 1, wherein in the preparation of 1-dimethylaminosulfonyl-2-amino--5 (6) - (a-methoxyiminobenzyl) benzimidazole, 2-amino- -5 (6) -benzoylbenzimidazole is reacted with a hydride with sodium and dimethylsulfamyl chloride and then with methoxyamine hydrochloride. 3. Process for the preparation of new carbonyl substituted 1-sulfonylbenzimidazoles of the general formula I, in which R is an alkyl group containing 1-4 carbon atoms or a group of the formula —NR3R4, in which R3 and R4 are independently alkyl groups containing 1-3 carbon atoms, R ± represents a hydrogen atom, R2 represents a hydrogen atom, an alkyl group containing 1-4 carbon atoms or a phenyl group, Z represents an alkoxyimino group in which the alkoxy group contains 1-4 carbon atoms or a benzyloxyimino group, a substituent of the formula 3 is in position 5 or 6, and n is the number 1, characterized in that the compound of general formula 2, in which R2 and n are as defined above, is reacted with a sulfonyl chloride of general formula RSO2C1 in which R is above the meaning given to give the intermediate of formula I, where Rt is hydrogen, Z is oxygen, and n, R and R2 are as defined above, which is reacted with hydroxylamine and then alkylated indirectly short Formula I wherein Z is hydroxyimino and the other symbols are as defined above to give the compound of Formula I wherein Z is an alkoxyimino group with 1-4 carbon atoms or a benzyloxyimino group. 4. The method of claiming 3. The process according to claim 3, characterized in that in the preparation of 1- (N, N-dimethylaminosulfonyl) -2-amino-5 (6) - (α-ethoxyiminobenzyl) benzimidazole, 2-amino-5 (6) -benzoylbenzimidazole is subjected to reaction with sodium hydride and dimethylsulfamyl chloride and then with hydroxylamine hydrochloride, then the obtained product is reacted with sodium methoxide and ethyl iodide. 5. The method according to p. 3. The process of claim 3, characterized in that in the preparation of 1- (N, N-dimethylaminosulfonyl) -2-amino -5 (6) - (α-propoxyiminobenzyl) benzimidazole, 2-amino-5 (6) -benzoylbenzimidazole is subjected to It is reacted with sodium hydride and dimethylsulfamyl chloride, and then with hydroxylamine hydrochloride, and the product obtained is reacted with sodium methanol and 1-iodopropane. FV \ C NHRi SOzR Formula 1 H Formula 2 M c - o ^ NH2 Formula H H »N- <S0aR XCH0 RSNH: 51 ^ 2 S0aR Rs H.N ^ J ^ H Scheme PL