KR800001138B1 - Process for carbonyl substituted-1-sulfenyl-benzmidazoles - Google Patents

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Description

Method for producing carbonyl-substituted-1-sulfonyl benzimidazoles

The present invention relates to a process for the preparation of the pharmacologically effective novel carbonylyl-substituted-1 sulfonylbenzimidazole compounds of formula (I).

은 5 또는 6위치에 존재해야 하며 이때의 n은 0 또는 1이며, 단 R₂가 1-(C_1-3알킬) 테트라졸-5-일 이거나 또는 1,3,4-옥사디아졸-2-일인 경우에는 n이 0이어야 한다.Wherein R is C _1-4 alkyl, C _5-7 cycloalkyl, thienyl, phenyl or —NR ₃ N ₄ where R ₃ , R ₄ are independently C _1-3 alkyl, R ₁ is hydrogen Or C _1-4 acyl, R ₂ is hydrogen, C _1-4 alkyl, phenyl, halophenyl, 1- (C _1-3 alkyl) tetrazol-5-yl, 1,3,4-oxadiazole- 2-1, or C _3-6 cycloalkyl, Z is oxygen, hydroxyimino, methoxycarbonyl oksiyi Mino, C _1-4 alkoxyimino, C _1-4 acyl oksiyi Mino, benzyl oksiyi Mino, benzoyl oksiyi unexposed, Hydrazono, thiocarbamyl hydrazono, carboxymethoxyimino, methoxycarbonylhydrazono, ethoxycarbonylhydrazono, carbamylhydrazono, 1,3-dithiolan-2-yl, 1 , 3-ditian-2-yl,

Must be in position 5 or 6, where n is 0 or 1, provided that R ₂ is 1- (C _1-3 alkyl) tetrazol-5-yl or 1,3,4-oxadiazole-2 N must be zero for -days.

The upper respiratory tract disease caused by the virus is very large, and nearly 100 million cases occur each year in the United States alone. A study in the UK (Tyrell and Brynoe, 1966) reports that 74 percent of cold patients are infected with rhinoviruses. More than 80 species of rhinoviruses have already been identified and identified, and the development of chemotherapeutic agents is becoming more urgent as there is no possibility of developing practical rhinovirus vaccines.

The virus growth inhibition of the compound in the laboratory can be easily tested by the virus anti-spot test described by Siminov (Applied Microbiology, 9 (1), 66 (1961)).

Some anti-fungal 1-dimethylaminosulfonyl-2-amino-benzimidazole compounds are described in US Pat. No. 3,853,908.

An object of the present invention is a novel benzimi that inhibits the growth of viruses, in particular rhinoviruses, polio viruses, coxsackie viruses, echo viruses and mengo viruses. It is to provide a method for producing a dozol compound.

The present invention reacts a compound of formula (II) with a compound of formula (III) to prepare a compound of formula (I) wherein R ₁ is hydrogen and Z is oxygen, optionally substituted amine, thiosemicarbazide Reacting with semicarbazide, hydrazine, substituted hydrazine, 1,3-propane dithiol or methanedithiol to produce a compound in which Z is not oxygen or a C _1-4 acyloxy imino group, optionally Z is hydroxyimide group in formula (I) by alkylating the compound Z is a C _1-4 alkoxyimino group is created and the following structural formula (I) compounds, acylated by Z is C _1-4 acyl oksiyi unexposed and / or R ₁ is C _1-4 The compound of formula (I), which is an acyl group, is prepared.

R ₁ , R ₂ and n in the above formula are as described above.

As used herein, "tautomer benzimidazole" refers to benzimidazole capable of hydrogen-substituting each nitrogen. Benzimidazoles having no substituent at the nitrogen moiety and having a substituent at the fifth position of the benzene residue also have a tautomeric form having a substituent at the sixth position. In this way, the isomer mixture may be labeled as 5 (6). As a result of such tautomers, the reaction of 5 (6) -substituted benzimidazole with sulfonylchloride of formula (III) yields an isomeric mixture of 5 (6) -substituted sulfonyl benzimidazole.

In the present invention, "thienyl" refers to a thiophene group bonded to 2- or 3-position, and "1,3-dithiolan-2-yl" refers to a 1,3-dithiolane group to 2-position. It means. In addition, "1,3-dityyn-2-yl" means that the 1,3-dithiane group is bonded at the 2-position, and "1- (C _1-3 alkyl) -tetrazol-5-yl" is 1 -Methyl-, 1-ethyl or 1-propyl-tetrazol group is bonded to the fifth position. "1,3,4-oxadiazol-2-yl" indicates that a 1,3,4-oxadiazole group binds to a second position.

In addition, “C _1-4 alkyl” herein refers to C _1-4 linear or branched alkyl including methylethyl, propyl, isopropyl, butyl, isobutyl, secondary butyl and tertiary butyl. In addition, "C _1-4 alkyl carbinol" refers to a linear or branched aliphatic alcohol having 1 to 4 carbon atoms as illustrated in "C _1-4 alkyl". “C _3-7 cycloalkyl” is saturated having 3 to 7 carbon atoms such as cyclopropyl, methylcyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1,2,3- or 4-methylcyclohexyl and cycloheptyl It means aliphatic ring. Also, "halophenyl" refers to the substitution of one chlorine or bromine at any position of phenyl. "C _1-4 alkoxy" refers to a straight or branched chain aliphatic ether group having 1 to 4 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy and secondary butoxy.

In addition, "C _1-4 alkylamino" refers to an aliphatic amine group having 1 to 4 carbon atoms derived from methylamine, ethylamine, propylamine, isopropylamine, butylamine, secondary-butylamine. In addition, "alkoxyamine" refers to a C1-C4 0-aliphatic hydroxylamine group derived from hydroxylamine. Methoxyamine hydrochloride is available on the market, and hydroxylamine derivatives can be alkylated and hydrolyzed with acetone oxime using (A) C _1-4 alkyl halides or with (B) -hydroxy phthalimide It can be prepared by alkylation and decomposition with hydrazine, or (c) alkylation and acid hydrolysis of benzohydrooxamic acid.

Suitable reactants are benzimidazole compounds having 5 (6) -substituents which do not react with sulfonyl chloride under the reaction conditions. Benzimidazole and sulfonyl chloride will usually use about the same mole number, but an excess of either compound may be used if necessary. The reaction proceeds in the presence of an inert solvent, such as acetone, tetrahydrofuran (THF), tertiary amide such as N, N-dimethylformamide (DMF), chlorinated hydrocarbons such as dichloromethane, dichloroethane and chloroform. You may add the base which acts as an acid binder to the reaction solution. Suitable bases for this purpose include pyridine, triethylamine, N-methylmorpholine, sodium bicarbonate, sodium hydride and the like. Preferred solvents for the reaction are acetone containing triethylamine or THF together with DMF containing sodium hydride as the base.

The reaction is best carried out at room temperature to the reflux temperature of the solvent used, and usually at 1 to 8 hours when the reaction is conducted at reflux temperature.

As a result of the above reaction, a 1-sulfonylbenzimidazole compound is produced, hereinafter referred to simply as a sulfonylbenzimidazole compound. The product can be separated by filtration, concentration and crystallization of the reaction mixture. The reaction mixture may also be evaporated to dryness and the residue treated with a suitable solvent such as acetone or methanol to remove insoluble matters. The solution containing the sulfonylbenzimidazole compound is concentrated to crystallize or evaporate to form a second residue which is dissolved in a solvent such as methanol and then recovered by crystallizing sulfonylbenzimidazole from methanol.

When the tautomer benzimidazole compound is reacted with sulfonyl chloride, sulfonyl benzimidazole isomers of 5-position and 6-position substitutions are generally produced in a ratio of 1: 1. These isomers are separated by fractional crystallization or column chromatography. Usually the 6-position isomer first crystallizes in solution. For example, when ethyl-2-amino-5-benziedazole carboxylate is reacted with dimethylsulfamoyl chloride in the presence of acetone containing triethylamine, ethyl-1-dimethylaminosulfonyl-2-amino-6- Benzimidazole carboxylate is preferentially crystallized from the reaction mixture. Acetone mother liquor mainly contains ethyl-1-dimethylaminosulfonyl-2-amino-5-benzimidazole carboxylate and some 6-positional isomers remain. Isomers can be identified by the spectrum of the phenyl moiety using an NMR apparatus (7.0 to 8.3 ppm)

Some of the compounds of formula (1) can be made by acylating, oxidizing or reducing the appropriate sulfonylbenzimidazole precursors. In this case, when the precursor is a mixture of isomers of sulfonyl imidazole, the resulting isomers can be separated by fractional crystallization or chromatography.

2-acylaminosulfonyl benzimidazoles wherein R ₁ is not hydrogen are made by acylating the corresponding 2-amino sulfonylbenzimidazole with a suitable acid anhydride. For example, 1-dimethylaminosulfonyl-2-amino-5 (6) -benzoyl benzimidazole isomeric mixture is stirred with acetic anhydride at room temperature to yield 1-dimethylaminosulfonyl-2-acetamido-5 (6)-. Benzoylbenzimidazole is produced in the form of a mixture. Isomers of 2-acetamidosulfonyl benzimidazole are separated by fractional crystallization from acetone, methanol or ethanol.

The synthesis reaction as described above can be carried out in several steps, and the benzimidazole can be chemically appropriately reacted with a suitable sulfonyl chloride to produce sulfonylbenzimidazole. Sulfonylbenzimidazole intermediates can also be made to chemically convert to the final product. Suitable benzimidazole reactants preferably have substituents capable of reacting with sulfonyl chloride before and after the reaction to allow 5 (6) -position substitution. Among them, ethyl esters of 2-substituted-5 (6) benzimidazole carboxylic acids are particularly suitable as reactants, since intermediates in which the ester groups can be easily converted to the final product after the reaction, as Because of making.

Ethyl ester intermediates or isomer mixtures of sulfonyl benzimidazole carboxylic acids, when reacted with hydrazine in a carbinol solvent, produce the corresponding hydrazides, respectively. For example, ethyl-1-dimethylaminosulfonyl-2-amino-5 (6) -benzimidazole carboxylate is refluxed with hydrazine hydrate in methanol to yield 1-dimethylaminosulfonyl-2-amino-5 (6)-. Benzimidazole carboxylic acid hydrazide is produced.

Such hydrazide compounds can be reacted with orthoesters, such as ethyl ortho formate, under heating to yield the corresponding 5 (6)-(1,3,4-oxadiazol-5-yl as in Scheme 1; ) Sulfonylbenzimidazole is produced. As an example, when 1-dimethylaminosulfonyl-2-acetamido-5 (6) -benzimidazole carboxylic acid hydrazide is refluxed with ethylortho formate, 1-dimethylaminosulfonyl-2-acetamido- 5 (6)-(1,3,4-oxadiazol-5-yl) sulfonylbenzimidazole is produced.

The 1-sulfonyl-2-substituted-5 (6) -benzimidazole carboxylic acid ethyl ester can also be reduced to the corresponding hydroxymethyl intermediate. As an example, ethyl-1-dimethylaminosulfonyl-acetamido-5 (6) -benzimidazole carboxylate can be reduced to 1-dimethyl in tetrahydrofuran with sodium-bis (2-methoxyethoxy) aluminum hydride. Aminosulfonyl-2-acetamido-5 (6) -hydroxymethyl benzimidazole is produced. A better way is to react the sulfonylchloride (RSO ₂ Cl) with a suitable 2-substituted-5 (6) -hydroxy methylbenzimidazole.

The required 5 (6) -hydroxy methylbenzimidazole reactant is sodium-bis (2-methoxyethoxy) -aluminum hydride to reduce ethyl-2-substituted 5 (6) -benzimidazole carboxylic acid in a nonpolar solvent. Make it. Large amounts of hydroxy methylsulfonyl benzimidazole intermediates are prepared starting from 4-chloro-3-nitrobenzyl alcohol. Treatment of such benzyl alcohol with ammonia yields 4-amino-3-nitro benzyl alcohol, and catalytic hydrogenation of the nitro benzyl alcohol produces 4-hydroxymethyl-0-phenylenediamine, which is benzyme Ring closure according to the known method of the doazole field yields the desired 2-substituted 5 (6) -hydroxymethylbenzimidazole intermediate.

In general, 5 (6) -hydroxymethyl sulfonylbenzimidazole compounds that can each be converted to the corresponding 5 (6) -formyl derivatives are important as intermediates. By oxidizing the hydroxymethyl carbanol functional group at this time, a carboxaldehyde compound having an unexpected viral growth inhibitory function is produced. In addition, the conversion of the carboxaldehyde functional group to the double bond of carbon-nitrogen can be seen that the antiviral efficacy is further increased.

The sulfonylbenzimidazole carboxaldehyde compound in which R ₂ is hydrogen oxidizes the hydroxy methyl group of 1-sulfonyl-2-substituted 5 (6) -hydroxymethyl benzimidazole in an aqueous solution of chromic acid and sulfuric acid as Jones reagent. Make. For example, when 1-dimethylaminosulfonyl-2-amino-5 (6) -hydroxymethyl benzimidazole is oxidized with Jones reagent, 1-dimethylaminosulfonyl-2-amino-5 (6) -formylbenzimimi Dazole is produced.

Since sulfonyl benzimidazole carboxaldehyde compounds are highly reactive with carboxyaldehyde groups, hydrazine, semicarbazide, thiosemicarbazide, hydroxylamine, benzyloxyamine, C _1-4 acyloxyamine, benzoyloxyamine , Methoxycarbonyl hydrazine, ethoxycarbonyl hydrazine, carboxymethoxyamine or C _1-4 alkoxyamine, when reacted in a conventional manner with 5 (6) -hydrazono methylene, 5 (6) -carbamylhydride. Lazonomethylene, 5 (6) -thiocarbamylhydrazonomethylene, 5 (6) -hydroxyiminomethylene, 5 (6) -benzyloxyiminomethylene, 5 (6) -C _1-4 acyloxyiminomethylene , 5 (6) -benzoyloxyiminomethylene, 5 (6) -methoxy carbonylhydrazonomethylene, 5 (6) -ethoxy carbonylhydrazonomethylene, 5 (6) -carboxymethoxy-imino Methylene or 5 (6) -C _1-4 alkyloxyiminomethylene derivatives and the like. 5 (6)-(1,3-dithiolane 2-yl) or 5 (6)-(1,3-dithia-2-yl) derivatives may be selected from 5 (6) -formylsulfonyl benzimidazole compounds. After conversion by reacting with 1,2-ethanedithiol or 1,3-propanedithiol in the presence of trifluoroeberate, the cyclic thioacetal product is recovered. This carbonyl reaction is described in Scheme 1.

[Schematic Table 1]

R ₅ = OH, O (C _1-4 ) alkyl, NH ₂ , NHC (O) NH ₂ , NHC (S) NH ₂ ,

OCH ₂ φ, OCH ₂ CO ₂ H, OC (O) (C _1-4 ) alkyl,

OC (O) φ, NHCO ₂ (C1-2) Alkyl

5 (6) -ketosulfonylbenzimidazole compounds in which Z is oxygen are made by reacting the corresponding 5 (6) -ketobenzimidazole with RSO ₂ Cl. Ketobenzimidazole reactants are made by treating the appropriate keto-0-phenylene diamine by known methods. In U.S. Patent Publication No. 93791, there is a description of the preparation method of keto-0-phenylenediamine having the following structural formula.

R ₂ in the above structure represents lower alkyl, cycloalkyl, phenyl or phenyl substituted with halogen, lower alkyl or lower alkoxy.

In the above preparation, 4-halo-3 prepared according to a Furidel-Craft reaction such as reacting 4-halo-3-nitrobenzoylchloride with a suitable hydrocarbon or reacting halobenzene with an acid chloride and then nitrating the aromatic ring. A method of ammonolysing and reducing nitrophenylketone. By this method, keto-0-phenylenediamine in which R ₂ is C _3-6 cycloalkyl can be prepared. Alternatively, the keto-benzimidazole reactant may be prepared by reacting acetanilide with a suitable derivative of C _2-8 alkanoic acid or C _3-6 cycloalkyl acid according to the Furidel-Craft acylation method. The 4-ketoacetanilide thus produced is nitrated to form 2-nitro-4-ketoanilide, and the acetanilide is hydrolyzed to form 2-nitro-4-ketoaniline.

Nitroaniline is catalytically hydrogenated to form 4-keto-0-phenylenediamine, which is closed to form 2-substituted-5 (6) -ketobenzimidazoles. The following specific example is a principle explanation for the preparation of 5 (6) -ketosulfonyl benzimidazole. The 4-propionyl acetanilide was nitrated at 0 ° C. to form 2-nitro-4-propionyl acetanilide, which was hydrolyzed and then catalytically hydrogenated to yield 4-propionyl-0-phenylenediamine. Is generated. Phenylenediamine is reacted with cyanogen bromide to form 2-amino-5 (6) -propionyl benzimidazole, and this propionylbenzimidazole is reacted with dimethylsulfamoyl chloride to produce 1-dimethylaminosulfonyl-2- Amino-5 (6) -propionyl benzimidazole is produced. In addition to sulfonylbenzimidazole carboxaldehyde, 5 (6) -ketosulfonyl benzimidazole is reacted with hydrazine, semicarbazide, thiosemicarbazide, hydroxylamine or C _1-4 alkoxyamine to give the corresponding hydrazone , Semicarbazone, thiosemicarbazone, oxime, C _1-4 alkoxyamine derivative or other derivatives can be made. However, ketocarbonyl functional groups are less reactive than carboxaldehyde functional groups.

As such, the keto functional group facilitates carbon-nitrogen double bond formation by protonating sulfonylbenzimidazole in the presence of an acid to increase activity.

Nitrogen functional groups are named according to the carbonylating agent from which they are derived and an example of some thereof is recorded as follows.

R ₃ is a heterocyclic oxadiazole or tetrazole sulfonyl benzimidazole is prepared according to the following method. The following example is for the preparation of 5 (6)-(1-alkyltetrazol-5-yl) -sulfonyl benzimidazole compound of formula (I). First, a 2-substituted 5 (6)-(1-alkyltetrazol-5-yl) -benzimidazole reactant is made according to the method of the examples described later. 4-aminobenzonitrile is acetylated and nitrated to form 3-nitro-4-acetaminobenzonitrile, which is reacted with sodium azide in dimethylformamide in the presence of ammonium chloride to give 5- (3- Nitro-4-acetamidophenyl) -tetrazole is produced, and the tetrazole portion is alkylated with methyl iodide in the presence of acetone and triethylamine to give 1 (2) -methyl-5- (3-nitro- 4-acetamidophenyl) tetrazole is produced in the form of a mixture of isomers. Hydrolysis of this tetrazole mixture with concentrated sulfuric acid over several hours at room temperature yields 1 (2) -methyl-5- (3-nitro-4-aminophenyl) tetrazole. At this time, the nitro group of the benzene portion is hydrogenated at 30 ° C. in the presence of ethanol-ethyl acetate under a palladium-carbon catalyst to give 1 (2) -methyl-5- (3,4-diaminophenyl) tetrazole. Reaction of this diaminophenyltetrazole with cyanogen bromide in the presence of methanol-water produces a predominantly methylisomer, 2-amino-5 (6)-(1-methyltetrazol-5-yl) benzimidazole. Reaction of benzimidazole with dimethylsulfonyl chloride in acetone in the presence of triethylamine results in 1-dimethylaminosulfonyl-2-amino-5 (6)-(1-methyltetrazol-5-yl) benzimidazole. Is generated. In addition, according to the method described above, the reaction of the appropriate 2-substituted 5 (6)-(1-alkyltetrazol-5-yl) benzimidazole reactants with sulfonyl chloride can be carried out by the other 5 (6)-of formula (I). A (1-alkyltetrazol-5-yl) -sulfonyl benzimidol compound is produced.

Benzimidazole compounds used as starting materials in the process can be prepared by a variety of methods known in the art of benzimidazole. Preparation of such benzimidazoles is well described in the chemistry of heterocyclic compounds of Weiss Burger, imidazole and derivatives thereof (Interscience Publishers Co. New York 1953). The 2-aminobenzimidazole reactants were prepared using Buttle, et al Bio. Chem. It may be made by ring closure by the method described in J. 32, 1101 (1938) and British Patent 551,524. Acylating the 2-aminobenzimidazole reactants with anhydrides of acetic acid or propionic acid also produces 2-acetamido or 2-propion amidobenzimidazole. The 2-formamidobenzimidazole reactant is made by reacting a mixed anhydride made from formic acid and acetic anhydride with 2-aminobenzimidazole. The 2-acylaminosulfonyl benzimidazole compounds may also be prepared by acylating the corresponding 2-aminosulfonylbenzimidazoles in the manner described above. Ethyl-2-amino-5 (6) -benzimidazole carboxylate is described by Paget et al. J. Med. Chem. 12, 1010 (1969), 2-amino-, 2-formamido, 2-acetamido- or reacted with a suitable sulfonylchloride and substituted with formyl, keto, etc. at the 5 (6) -position. 2-propionamido benz imidazole etc. can be made.

Sulfonyl chlorides required as reactants [eg methanesulfonyl chloride (methyl chloride), isopropyl sulfonyl chloride, dimethylsulfamoyl chloride, benzenesulfonyl chloride, 2-thiophenesulfonyl chloride] can be purchased commercially. Other C _1-4 alkyl or C _5-7 cycloalkyl sulfonylchlorides can also be prepared by chlorinating the appropriate alkylthiols or by reacting sodium alkylsulfonates made of carbinol and sulfuric acid with sulfuryl chloride.

N, N-diylkilsulfamoyl chloride is described in Bindely et al. J. Am. Chem. Soc. Prepared by reacting secondary amine salts with sulforyl chlorides in the manner described in 61, 3250 (1939). These compounds are also made by reacting chloroamines of the formula such as R ₃ R ₄ N-Cl with sulfur dioxide at -5 ° to 30 ° C. Such chloroamine compounds are made by reacting the corresponding secondary amines with antimony pentaoxide, sodium hypochloride or sulfonyl chloride.

As described above, sulfonyl chlorides that can react with benzimidazoles include ethyl-, propyl-, isopropyl-, butyl-, isobutyl-, and secondary butyl in addition to cyclopentyl-, cyclohexyl- and cycloheptyl sulfochlorides. Tert-butyl sulfonyl chloride.

Another sulfamoyl is diethyl-, dipropyl, N-methyl-N-ethyl-, N-methyl-N-propyl-, N-ethyl-N-propyl, N-methyl-N-isopropyl, N- Ethyl-N-isopropyl, N-propyl-N-isopropyl-, diisopropyl sulfamoyl chloride and the like.

In order to harmonize the naming, sulfonyl benzimidazoles are simply named sulfonyl derivatives. In one example, the compound produced by the reaction of dimethylsulfamoyl chloride and 2-amino-5-benzoylimidazole is not referred to as 1-dimethylsulfamoyl-2-amino-5 (6) -benzoylbenzimidazole but is 1-dimethyl. Aminosulfonyl-2-amino-5 (6) -benzoylbenz imidazole is named.

As a sulfonyl benzimidazole compound preferable also in a structural formula (1) compound,

R is isopropyl or dimethylamino, R ₁ is hydrogen or formyl, R ₂ is phenyl, hydrogen, propyl or P-chlorophenyl, n is 1, Z is oxygen, hydroxyimino, C _1-3 Alkylimino, C _1-3 acyloxyimino or thiocarbamylhydrazonoin compound.

Specific examples of the preferred compounds as described above are as follows.

1-dimethylaminosulfonyl-2-amino-5 (6)-(α-hydroxyamino-4-chlorobenzyl) benzimidazole,

1-dimethylaminosulfonyl-2-amino-5 (6)-(α-methoxyiminobenzyl) benzimidazole,

1-dimethylaminosulfonyl-2-amino-5 (6)-(α-thiocarbamylhydrazonobenzyl) imidazole.

Examples of esters, hydrazides, and hydroxymethyl intermediates used when preparing the compound of formula (1) include the following compounds.

Ethyl 1-isopropanesulfonyl-2-amino-5 (6) -benz imidazole carboxylate,

Ethyl 1- (N-methyl-N-propylaminosulfonyl) -2-formamido-5 (6) -benzimidazole carboxylate,

Ethyl 1- (N-methyl-N-ethylaminosulfonyl) -2-formamido-5 (6) -benzimidazole carboxylate,

Ethyl 1-butanesulfonyl-2-propionamido-5 (6) -benzimidazole carboxylate,

Ethyl 1-cyclohexanesulfonyl-2-amido-5 (6) -benzimidazole carboxylate,

Ethyl 1- (2-thiophene) sulfonyl-2-acetamido-5 (6) -benzimidazole carboxylate,

Ethyl 1- (N-ethyl-N-propylaminosulfonyl) -2-amino-5 (6) -benzimidazole carboxylate,

Ethyl 1-isobutanesulfonyl-2-propionamino-5 (6) -benzimidazole carboxylate,

Ethyl 1- (2-thiophene) sulfonyl-2-acetamino-5 (6) -benzimidazole carboxylate,

Ethyl 1-dimethylaminosulfonyl-2-propionamino-5 (6) -benzimidazole carboxylate,

1-isopropanesulfonyl-2-amino-5 (6) -benzimidazole carboxylic acid hydrazide,

1-benzylsulfonyl-2-propionamido-5 (6) -benzimidazole carboxylic acid hydrazide,

1- (N-methyl-N-propylaminosulfonyl) -2propionamido-5 (6) -benzimidazole carboxylic acid hydrazide,

1-diisopropylaminosulfonyl-2-amino-5 (6) -benzimidazole carboxylic acid hydrazide,

1-diethylaminosulfonyl-2-amino-5 (6) -benzimidazole carboxylic acid hydrazide,

1-pentanesulfonyl-2-formamido-5 (6) -benzimidazole carboxylic acid hydrazide,

1-ethanesulfonyl-2-propionamido-5 (6) -hydroxy methylbenz imidazole,

1-cyclopropanesulfonyl-2-amino-5 (6) -hydroxy methylbenz imidazole,

1-benzenesulfonyl-2-formamino-5 (6) -hydroxymethylbenz imidazole,

1- (N-methyl-N-propylaminosulfonyl) -2-acetamino-5 (6) -hydroxymethylbenz imidazole,

1-dipropylaminosulfonyl-2-propionamino-5 (6) -hydroxymethylbenz imidazole,

1-isobutanesulfonyl-2-acetamino-5 (6) -hydroxy methylbenzimidazole,

1-cyclopentanesulfonyl-2-propionamino-5 (6) -hydroxymethyl benzimidazole,

1- (N-ethyl-N-propylamidosulfonyl) -2-formamido-5 (6) -hydroxy methylbenzimidazole,

1-benzenesulfonyl-2-propionamido-5 (6) -hydroxy methylbenzimidazole,

1-cyclohexanesulfonyl-2-formamido-5 (6) -hydroxy methylbenzimidazole,

1-diethylaminosulfonyl-2-acetamido-5 (6) -hydroxymethyl benzimidazole,

1-cycloheptansulfonyl-2-propionamido-5 (6) -hydroxymethyl benzimidazole,

1-diethylaminosulfonyl-2-amino-5 (6) -hydroxy methylbenzimidazole,

1- (N-ethyl-N-isopropylaminosulfonyl) -2-formamido-5 (6) -hydroxymethylbenz imidazole.

The 5 (6) -formylsulfonylbenz imidazole compounds and their derivatives are specifically listed as Structural Formula (1) as follows.

1-cyclohexanesulfonyl-2-formamido-5 (6) -formylbenzimidazole,

1-diethylaminosulfonyl-2-acetamido-5 (6) -formylbenzimidazole,

1-cyclopentanesulfonyl-2-acetamido-5 (6) -formylbenzimidazole,

1- (2-thiophene) sulfonyl-2-propionamido-5 (6) -formylbenzimidazole,

1-benzenesulfonyl-2-amino-5 (6) -formylbenzimidazole,

1-butanesulfonyl-2-amino-5 (6) -formylylbenzimidazole,

1-methanesulfonyl-2-acetamido-5 (6) -formylbenzimidazole,

1-isopropanesulfonyl-2-propionamido-5 (6) -formylbenzimidazole,

1- (2-thiophene) sulfonyl-2-amino-5 (6) -formylbenzimidazole,

1-cyclopentanesulfonyl-2-acetamido-5 (6) -formylbenzimidazole,

1-isopropanesulfonyl-2-amido-5 (6) -formylbenzimidazole,

1-ethanesulfonyl-2-formamido-5 (6) -formylbenzimidazole,

1-benzenesulfonyl-2-propionamido-5 (6) -formylbenzimidazole,

1-dipropylaminosulfonyl-2-acetamido-5 (6) -formylbenzimidazole,

1-dimethylaminosulfonyl-2-propionamido-5 (6)-(isopropoxy iminomenyl) benzimidazole,

1-isopropanesulfonyl-2-amido-5 (6)-(1,3-dithia-2-yl) benzimidazole,

1-dimethylaminosulfonyl-2-propionamido-5 (6)-(methoxyimino methyl) benzimidazole,

1-benzenesulfonyl-2-formamido-5 (6)-(hydroxyimido methyl) benzimidazole,

1-isopropanesulfonyl-2-amino-5 (6)-(hydroxyimino methyl) benzimidazole,

1-isopropanesulfonyl-2-acetamino-5 (6)-(hydrazonomethyl) benzimidazole,

1-dimethylaminosulfonyl-2-amino-5 (6)-(hydrazono methyl) benzimidazole,

1-dimethylaminosulfonyl-2-acetamido-5 (6)-(carbamylhydrazonomethyl) benzimidazole,

1-dimethylaminosulfonyl-2-amino-5 (6)-(thiocarbamylhydrazonomethyl) benzimidazole,

1-dimethylaminosulfonyl-2-acetamido-5 (6)-(hydroxyimino methyl) benzimidazole,

1-dimethylaminosulfonyl-2-amino-5 (6)-(methoxyimino methyl) benzimidazole,

1-dimethylaminosulfonyl-2-acetamido-5 (6)-(ethoxyimino methyl) benzimidazole,

1-diisopropyl aminosulfonyl-2-propionamido-5 (6)-(propoxyamino methyl) benzimidazole,

1-dimethylaminosulfonyl-2-acetamido-5 (6)-(butoxyimino methyl) benzimidazole,

1- (2-thiophene) sulfonyl-2-acetamido-5 (6)-(secondary-butoxyimino methyl) benzimidazole,

1-dimethylaminosulfonyl-2-amido-5 (6)-(1,3-dithiolan-2-yl) benzimidazole,

1-dimethylamino-2-acetamido-5 (6)-(1,3-ditian-2-yl) benzimidazole,

1-isopropanesulfonyl-2-acetamido-5 (6)-(1,3-ditian-2-yl) benzimidazole,

1-cyclohexanesulfonyl-2-formamido-5 (6)-(1,3-ditian-2-yl) benzimidazole.

The 5 (6) -ketosulfonylbenzimidazole compounds and derivatives thereof as the structural formula (1) are specifically listed as follows.

1-isopropanesulfonyl-2-amino-5 (6) -acetylbenzimidazole,

1-cyclopentanesulfonyl-2-acetamido-5 (6) -propionylbenzimidazole,

1-cyclopentanesulfonyl-2-formamido-5 (6) -isopropionylbenzimidazole,

1-dimethylaminosulfonyl-2-acetamido-5 (6) -butylylbenzimidazole,

1-diethylaminosulfonyl-2-amino-5 (6) -pentanoylbenzimidazole,

1-dimethylaminosulfonyl-2-amino-5 (6) -cyclopropylcarbonylbenzimidazole,

1-diethylaminosulfonyl-2-amino-5 (6) -cyclopropylcarbonylbenzimidazole,

1- (2-thiophene) sulfonyl-2-acetamido-5 (6) -cyclobutylcarbonylbenzimidazole,

1-cyclohexanesulfonyl-2-acetamido-5 (6)-(1-hydroxyiminopropyl) benzimidazole,

1-isopropanesulfonyl-2-propionamido-5 (6)-(1-methoxyiminoisopropyl) benzimidazole,

1-dimethylaminosulfonyl-2-amino-5 (6)-(1-ethoxyiminobutyl) benzimidazole,

1-benzenesulfonyl-2-acetamido-5 (6)-(1-butoxyiminohexyl) benzimidazole,

1-dimethylaminosulfonyl-2-amino-5 (6)-(α-hydrazonocyclopentylmethyl) benzimidazole,

1-cyclobutanesulfonyl-2-acetamido-5 (9)-(α-hydroxy iminocyclobutylmethyl) benzimidazole,

1-diethylaminosulfonyl-2-propionamido-5 (6)-(α-ethoxyiminocyclohexylmethyl) benzimidazole,

1-dimethylaminosulfonyl-2-amino-5 (6)-[α- (thiocarbamylhydrazono) cyclopentylmethyl] benzimidazole,

1-diidisopropyl aminosulfonyl-2-acetamido-5 (6)-[α- (carbamylhydrazono) cyclobutylmethyl] benzimidazole,

1-dimethylaminosulfonyl-2-amino-5 (6)-(1-hydrazonopropyl) benzimidazole,

1-cycloheptansulfonyl-2-formamido-5 (6)-(1-carbamylhydrazonoethyl) benzimidazole,

1- (2-thiophene) sulfonyl-2-propionamido-5 (6)-(1-thiocarbamyl hydrazonoethyl) benzimidazole,

1-dimethylaminosulfonyl-2-amino-5 (6)-[(α-ethoxyimino) cyclohexylmethyl] benzimidazole,

1-dimethylaminosulfonyl-2-amino-5 (6) -cyclopropylacetylbenzimidazole,

1-isopropanesulfonyl-2-acetamido-5 (6) -cyclobutylacetylbenzimidazole,

The 5 (6) -heterocyclic sulfonylbenzimidazole compounds as the structural formula (1) compound include the following compounds.

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

1-butanesulfonyl-2-formamido-5 (6)-(1,3,4-oxadiazol-2-yl) benzimidazole,

1-benzenesulfonyl-2-acetamido-5 (6)-[1 (2) -propyltetrazol-5-ylbenzimidazole,

1-diisopropylaminosulfonyl-2-acetamido-5 (6)-[1 (2) -ethyltetrazol-5-yl] benzimidazole,

1-isopropanesulfonyl-2-acetamido-5 (6)-[1 (2) -methyltetrazol-5-yl] benzimidazole,

1-cycloheptansulfonyl-2-amido-5 (6)-[1 (2) -propyltetrazol-5-yl] benzimidazole.

Examples of the 5 (6) -hydroxysulfonynilbenzimidazole compounds and esters thereof as the structural formula (1) compound are as follows.

1-ethanesulfonyl-2-amino-5 (6) -hydroxybenzimidazole,

1-isopropanesulfonyl-2-formamido-5 (6) -hydroxybenzimidazole,

1-cyclohexanesulfonyl-2-amino-5 (6) -hydroxybenzimidazole,

1-benzenesulfonyl-2-formamido-5 (6) -hydroxybenzimidazole,

1- (2-thiophene) sulfonyl-2-propionamino-5 (6) -hydroxybenzimidazole,

1-diisopropylaminosulfonyl-2-acetamido-5 (6) -hydroxybenzimidazole,

1- (N-methyl-N-isopropylaminosulfonyl) -2-propionamido-5 (6) -hydroxybenzimidazole,

1-cyclopentanesulfonyl-2-propionamido-5 (6) -acetoxybenzimidazole.

The following example relates to the starting material and the intermediate material for the structural formula (1), which is a novel compound of the present invention, and a method for preparing the compound itself, wherein “m / e” is the mass of ions appearing in the mass spectrum of the product. The ratio of charge to charge is generally the value corresponding to the molecular weight of the main peak.

Example 1

140 g (0.68 mole) of ethyl-2-amino-5 (6) -benzimidazole carboxylate are stirred with 77 ml of triethylamine and 500 ml of acetone. While stirring the mixture, 140 g of dimethylsulfamoyl chloride in 100 ml of acetone was added and dissolved through a dropping noodle. The reaction mixture is refluxed for about 100 hours and filtered into a hot mixture to yield solid A. The filtrate is cooled and left overnight to crystallize solid B. Solids A and B were combined and washed with water to remove triethylamine hydrochloride. This product is dissolved in 1.5 L of absolute ethanol and the hot ethanol solution is filtered to remove insoluble matters. The ethanol filtrate is cooled to allow the pure product to crystallize. As a result, 23 g of ethyl-1-dimethylamino sulfonyl-2-amino-6-benzimidazole carboxylate (melting point: 215 to 217 ° C) was produced.

Assay: C ₁₂ H ₁₆ H ₄ O ₄ S Theoretical: C46.14, H 5.16, N 17.94

Molecular weight: 312 Sense: 45.87, 5.05, 18.21

Evaporation of the ethanol filtrate yields 55 g of 5-isomer and ethyl-1-dimethylaminosulfonyl-2-amino-5-benzimidazole carboxylate (melting point: 167-168 ° C.). The 5-isomer was analyzed by NMR and elemental analysis, yielding 18g of 18% of the total yield.

Example 2-8

The following ethyl-1- (substituted-sulfonyl) -2-amino-5 (6) -benzimidazole carboxylates were prepared according to the method of Example 1.

In the above table, ^* means 5-isomer, ^** means 6-isomer, and others indicate 5 (6) -isomer mixture.

The final compounds made in Examples 1-8 can be reduced according to the method of Example 9 to make the corresponding 5 (6) -hydroxymethyl sulfonylbenzimidazole compounds.

Example 9

(A) 2-Amino-5 (6) -hydroxymethylimidazole

24.6 g of methyl-2-amino-5 (6) -benzimidazole, carboxylate are suspended in 600 ml of THF in the presence of nitrogen. To this reaction mixture was added 96 ml of sodium bis (2-methoxyethoxy) -aluminum hydride (RED-AL) dissolved in 400 ml of THF.

The mixture is refluxed for about 20 hours and excess RED-AL is decomposed by adding 30 ml of water. The mixture is then filtered and the filtrate is evaporated to dryness. The foamy residue is treated with 150 ml of ethyl acetate and 200 ml of water. Separation and filtration of the aqueous phase of the emulsion phase yields a yellow solid. The aqueous solution is evaporated in vacuo to give a second product. Combined yield yields 12.3 g (65%) of crude 2-amino-5 (6) -hydroxymethylbenzimidazole. From this, a sample for analysis of the isomeric mixture was prepared.

Assay: C ₈ H ₉ N ₃ O Theory: C 58.88, H 5.56, N 25.75

Molecular weight: 163 Found: 58.65, 5.48, 25.54

(B) 1-dimethylaminosulfonyl-2-amino-5 (6) -hydroxymethylbenzimidazole

4.9 g (0.03 mol) of 2-amino-5 (6) -hydroxymethylbenzimidazole and 3.03 g (0.03 mol) of triethylamine are dissolved in 40 ml of acetone. To this was added 4.32 g (0.03 mol) of dimethylsulfonylchloride and refluxed for 17 hours. 25 ml of water is added thereto, followed by extraction with chloroform. The chloroform extract is washed with water and washed with saturated sodium chloride solution. After filtration and drying of the chloroform solution, the chloroform was evaporated in vacuo to yield 5.5 g (66%) of the crude product. 7 g of the crude product was subjected to silica gel chromatography using ethyl acetate as eluent. 6 liters of eluent (ethyl acetate) were passed through to obtain 1.2 g of 6-isomer 1-dimethylaminosulfonyl-2-amino-6-hydroxy methylbenzimidazole.

Melting point: 182-183 ° C. (ethyl acetate-methanol recrystallization) Molecular weight: 270 Theoretical value: C 44.43, H 5.22, N 20.73

Found: 44.43, 5.18, 20.44

Example 10

(A) 4-amino-3-nitrobenzyl alcohol

50 g (0.27 mole) of 4-chloro-3-nitrogenzyl alcohol, 250 ml of methanol and 200 ml of ammonia were placed in a cold autoclave and heated to 150 ° C. for 6 hours. After cooling again, the contents were taken out and evaporated in vacuo, and the obtained residue was put in ether, and the solution was filtered to remove ammonium chloride. The ether filtrate is evaporated in vacuo to give a solid product which is then recrystallized from ethanol-ethyl acetate to give 23.6 g (52%) of 4-amino-3-nitrobenzyl (melting point 100-101 ° C.).

Assay: C ₇ H ₈ N ₂ O ₄ Theory: C 50.00, H 4.80, N 16.66

Molecular weight: 168 Found: 49.72, 4.56, 16.44

(B) 3,4-diaminobenzyl alcohol

At a temperature of room temperature, 5 g of rannickel, 95 ml of THF, and 6 g of 4-amino-3-nitrobenzyl alcohol were hydrogenated at a pressure of 2.74 x 10 dyne / cm 2, but proceeded until 3 mol of hydrogen was absorbed. After completion of the reaction, the catalyst was removed and the filtrate was evaporated in vacuo to yield 4.83 g (82%) of 3,4-diaminobenzyl alcohol with a melting point of 74 to 75 ° C.

Assay: C ₇ H ₁₀ N ₂ O Theoretic: C 60.85, H 7.30, N 20.28

Molecular weight: 138 Found: 60.90, 7.75, 19.99

(C) 2-amino-5 (6) -hydroxymethylbenzimidazole

Dissolve 2 g (0.014 mol) of 3,4-diamino benzyl alcohol in 40 ml of methanol. To this was added 1.6 g of a cyanogen bromide solution in 10 ml of methanol. Vacuum evaporation of the mixture after standing overnight at room temperature yields 3.4 g (97%) of the hydrobromide salt of compound (C).

Alternatively, the product is separated by the above method by treating the filtrate with only cyanobromide with a filtrate which removes only the catalyst component without separating the intermediate diamine after hydrogenating 4-amino-3-nitrobenzyl alcohol. The final product can be obtained.

Example 11

250 mg of 1-dimethylaminosulfonyl-2-5 (6) -hydroxymethylbenzimidazole in 7 ml of acetone is suspended and cooled in an ice bath. About 0.3 ml of Jones is added and the reaction is continued at 0 ° C. for about 5 minutes. The mixture was poured into 40 ml of water, the liquid layer was extracted with 40 ml of chloroform, washed with water, washed with saturated sodium chloride solution and dried. Evaporation of chloroform under vacuum left a solid residue which was recrystallized from ethyl acetate to yield 57 mg (first batch) of 1-dimethylaminosulfonyl-2-amino-5 (6) -formylbenzimidazole.

Assay: C ₁₀ H ₁₂ N ₄ O ₃ S Theoretical: C 44.71, H 4.51, N 20.88

Molecular weight: 268 Found: 44.75, 4.52, 20.63

Example 12

268 mg (0.001 mol) of 1-dimethylaminosulfonyl-2-amino-5 (6) -formylbenzimidazole, 101 mg (0.001 mol) of triethylamine, and 69 mg (0.001 mol) of hydroxyl amine hydrochloride Five drops of water are refluxed for about 20 hours. The reaction mixture is cooled and filtered to give 140 mg of 1-dimethylaminosulfonyl-2-amino-5 (6)-(hydroxyiminomethyl) benzimidazole. The filtrate is poured into 30 ml of water and the liquid mixture is extracted as ethyl acetate. The organic layer is washed with water and dried over magnesium sulfate. Evaporation of ethyl acetate in vacuo yields 87 mg of an oxime compound.

Assay: C ₁₀ H ₁₃ N ₅ O ₃ S Theoretic: C 42.55, H 4.28, N 24.81

Molecular weight: 263 found: 42.03, 4.31 23.91

Example 13

268 mg (0.001 mol) of 1-dimethylaminosulfonyl-2-amino-5 (6) -formylbenzimidazole, 20 mg of methanol and 32 mg of hydrazine are refluxed for 16 hours. The reaction mixture is evaporated to a quarter of the original volume. Add 30 ml of water and take the precipitate to produce 80 mg of 1-dimethylaminosulfonyl-2-amino-5 (6)-(hydrazonomethyl) benzimidazole. The aqueous filtrate was dried in vacuo to yield more 75 mg of hydrazine derivative.

m / e 282.

Example 14

250 mg of 1-dimethylaminosulfonyl-2-amino-5 (6) -formylbenzimidazole and 15 ml of methanol and 70 mg of thiosemicarbazide are refluxed together for 3 hours. This thiosemicarbazone is precipitated by cooling and the amount is 170 mg of solid. Recrystallization of thiosemicarbazone with methanol / chloroform (6 ml / 2 ml) yields 100 mg of 1-dimethylaminosulfonyl-2-amino-5 (6) -thiocarbamylhydrazono methylenebenzimidazole.

Assay: C ₁₁ H ₁₅ N ₇ O ₂ S ₂ Theoretic: C 38.70, H 4.43, N 28.72

Molecular weight: 341 Found: 38.87, 4.64, 28.57

Example 15

536 mg (0.002 mol) of 1-dimethylaminosulfonyl-2-amino-5 (6) -formylbenzimidazole, 4 ml of methanol, 222 mg of semicarbazide and 0.5 ml of water are refluxed for 2 hours. 2 ml of methanol is added to the cooled mixture to allow the product to precipitate. The product is washed with cold methanol to give 226 mg of semicarbazone. The combined filtrates are evaporated in vacuo to reduce the volume, the residue is treated with 50 ml of saturated sodium chloride solution and the aqueous solution is extracted with methylene chloride. The extract was washed with water, washed with saturated brine and dried, and then methylene chloride was evaporated in vacuo to further 160 mg of 1-dimethylaminosulfonyl-2-amino-5 (6) -carbamylhydrazono methylene benzimidazole. Get

m / e 325.

Example 16

268 mg (0.001 mole) of 1-dimethylaminosulfonyl-2-amino-5 (6) -formylbenzimidazole, 5 ml of methanol, 0.2 ml of ethanethiol, and 0.2 ml of boron trifluoride were added, and at room temperature, about 2 Reaction over time. The resulting precipitate was filtered off and the solid was washed with cold methanol to give 65 mg of cyclic thioaceral, 1-dimethylaminosulfonyl-2-amino-5 (6)-(dithiolan-2-yl) benzimidazole. Got it. The washing solution and the filtrate are combined, 20 ml of saturated sodium carbonate solution is added thereto, the aqueous layer is extracted as ethyl acetate, washed with saturated sodium chloride solution and dried over magnesium sulfate. The solid residue obtained by vacuum evaporation of etaacetate was treated with methanol and 1-dimethylaminosulfonyl-2-amino-5 (6)-(1,3-dithiolan-2-yl) was obtained by taking a substance insoluble in methanol. 155 mg of benzimidazole are produced. Vacuum evaporation of the methanol filtrate yields an additional 95 mg.

m / e 344.

Example 17

220 mg (0.0008 moles) of 1-dimethylaminosulfonyl-2-amino-5 (6) -formylbenzimidazole with 2 ml of methanol and 0.15 ml of 1,3-propanedithiol and 0.75 ml of boron trifluoride React at room temperature. About 6 ml of ether is added to the mixture and the reaction is continued for 2 hours. Ether is added to the mixture to dilute the volume to 12 ml and the product precipitates out of solution. Centrifuge the mixture and discard the supernatant. The precipitate is suspended in ether and centrifuged again. Discarding the supernatant again and vacuum drying the solid product gave 224 mg (75%) of cyclic thioacetal product, 1-dimethylaminosulfonyl-2-amino-5 (6)-(1.3-dithia-2--2-) benzimidazole Is generated.

m / e 358

Example 18

135 ml of a solution of methoxyaminehydrochloride and 1-dimethylaminosulfonyl-2-amino-5 (6) -formylbenzoimidazole in 20 ml of methanol are refluxed for 17 hours. The color of the solution changed from red to yellow and the reaction mixture was concentrated to 1/2 volume and 9 ml of buffer (pH7) was added. The mixture was evaporated by filtration, washed with water and dried to give 42 mg of 1-dimethylaminosulfonyl-2-amino-5 (6)-(methoxyaminomethyl) benzimidazole.

m / e 297.

Example 19

(A) 4-acetamido acetophenone

100 g of P-aminoacetophenone is added dropwise to 400 ml of acetic anhydride. After adding pyridine to a homogeneous solution, the reaction mixture was stirred at room temperature for 2 hours, and when placed in 3.5 L of cold water, 108.5 g (93%) of 4-acetamido acetophenone was deposited.

Assay: C ₁₀ H ₁₁ NO ₂ Theoretic: C 68.78, H 6.26, N 7.90

Molecular weight: 177 found 68.03, 6.47, 8.02

(B) 3-nitro-4-acetamido acetophenone

5 g of 4-acetamidoacetophenone are slowly added to 25 ml of fuming nitric acid, maintaining 0 ° to 5 ° C. At the end of the stock price, the mixture is stirred for 15 minutes and carefully poured on ice. 4.7 g (75%) of 3-nitro-4-acetamidoacetophenone is precipitated out.

(C) 3-nitro-4-aminoacetophenone

16 g of 3-nitro-4-acetamidoacetophenone is added to 160 ml of concentrated sulfuric acid, and the mixture is stirred at room temperature for about 1 hour. The mixture is poured into cold water and the precipitate is taken to yield 9.5 g (73%) of 3-nitro-4-aminoacetophenone.

Assay: C ₈ H ₈ N ₂ O ₃ Theoretic: C 53.33, H 4.48, N 15.55

Molecular weight: 180 found: 53.18 4.43 15.87

(D) 2-amino-5 (6) -acetylbenzimidazole

4.5 g of 3-nitro-4-aminoacetophenone is hydrogenated in 145 ml of ethyl acetate at room temperature and 4.13 × 10 ⁶ dyne / cm 2 using 1 g of platinum oxide catalyst and 3 g of Lannickel catalyst. If 3 equivalents of hydrogen are absorbed in 5 hours, the catalyst is removed and 3 g of cyanogen bromide is added to the filtrate and stirred for 24 hours. 2 g of 2-amino-5 (6) -acetylbenzimidazole is precipitated in the form of embrittlement hydrochloride.

Assay: C ₉ H ₉ N ₃ O Hbr Theoretic: C 42.21, H 3.94, N 16.41

Molecular weight: 256 Found: 42.43 4.09 16.35

(M) 1-Dimethylaminosulfonyl-2-amino-5 (6) -acetylbenzimidazole 4 g (0.0156 mol) of 2-amino-5 (6) -acetylbenzimidazole embrittlement hydrochloric acid and 50 ml of acetic acid and 5 ml Triethylamine and 2.3 g (0.016 mol) of dimenylsulfonyl chloride were refluxed for 12 hours. 80 ml of methanol was poured into the residue obtained by vacuum evaporation of the filtrate from which the mixture was filtered, concentrated to 60 ml, and cooled. Yellow crystal 1-dimethylaminosulfonyl-2-5 (6) having a melting point of 206 to 210 캜 (decomposition). 800 mg of aminoacetylbenzimidazole is produced.

Assay: C ₁₁ H ₁₄ N ₄ O ₃ Theoretic: C 46.80, H 5.00, N 19.85

Molecular weight 282 found: 47.70 4.99, 19.65

Example 20

(A) 10 g (0.053 mole) of 2-amino-5 (6) -propionyl benzimidazole with 100 ml of acetone, 10 ml of triethylamine and 8.6 g of dimethylsulfamoyl chloride to form a crude product, Recrystallization from methanol yields 6.0 g of 1-dimethylaminosulfonyl-2-amino-5-propionyl benzimidazole, a 5-isomer having a melting point of 206 to 208 ° C.

Assay: C ₁₂ H ₁₈ N ₄ O ₃ S Theoretical: C 48.64, H 5.44, N 18.91

Molecular weight 296 found: 48.41, 5.49, 18.73

(B) NMR confirmed that 2.8 g of a material insoluble in methanol in the above determination was 1-dimethylaminosulfonyl-2-amino-6-propionyl benzimidazole as a 6-isomer.

Assay: C ₁₂ H ₁₈ N ₄ O ₃ S Theory: c 48.64, H 5.44, N 18.91

Molecular weight 296 found: 48.58, 5.63, 18.71

Example 21

According to the method of Example 19, 292 g of 1-dimethyl was reacted with 5.7 g of 2-amino-5 (6) -butyryl benzimidazole, 30 ml of acetone, 5.7 g of triethylamine, and 4 g of dimethylsulfamoylchloride. Aminosulfonyl-2-amino-5 (6) -butyryl benzimidazole is produced.

Assay: C ₁₃ H ₁₈ N ₄ O ₃ S Theory: C 50.31, H 5.05, N 18.05

Molecular weight 310 found: 49.93, 5.73, 17.84

Example 22

423 g of 1-dimethylaminosulfonyl-2-amino-5 (6) -acetyl benzimidazole, 300 mg of hydroxyl aminehydrochloride, and 60 ml of methanol were refluxed together for 17 hours. The solution is concentrated in a steam bath to half its volume. 30 ml of buffer (pH 7) was added thereto, and the resulting solid was filtered to give 1-dimethylaminosulfonyl-2-amino-5 (6)-(α-hydroxyiminoethyl) benzimidazole (melting point 222 to 225). 318 mg) is produced.

Example 23

A solution of 141 mg (0.5 mmol) of 1-dimethylaminosulfonyl-2-amino-5 (6) -acetylbenzimidazole, 120 mg of methoxyamine hydrochloride and 20 ml of methanol was refluxed for 19 hours. The solution is concentrated to a volume of 1/2, and the same amount of water is added until a solid appears. 5 ml of buffer (pH7) was added thereto, filtered and washed twice with 75 mg of 1-dimethylaminosulfonyl-2-amino-5 (6)-(α-methoxyiminoethyl) benzimidazole (melting point). : 183 to 185 ° C.) is produced.

Assay: C ₁₂ H ₁₇ N ₅ O ₃ S Theory: C 46.29, H 5.56, N 22.49

Molecular weight 311 found: 46.50, 5.34, 22.22

Example 24

423 mg of 1-dimethylaminosulfonyl-2-amino-5 (6) -acetylbenzimidazole, 300 mg of thiosemicarbazide and 1.5 ml of 1N hydrochloric acid were refluxed together with 60 ml of methanol for 16.5 hours. The solution was concentrated, precipitated by addition of 30 ml of buffer (pH 7) and dried to give 360 mg of 1-dimethylaminosulfonyl-2-amino-5 (6)-(α-thiocarbarylhydrazonoethyl) benzimidazole (melting point: 230 to 235 ° C. decomposition) is produced.

Assay: C ₁₂ H ₁₇ N ₇ O ₂ S ₂ Theoretic: C 40.55, H 4.82, N 27.59

Molecular weight 355 found: 40.22, 4.50, 27.27

Example 25

148 mg (0.05 mmol) of 1-dimethylaminosulfonyl-2-amino-5 (6) -propionyl benzimidazole, 100 mg of thio semicarbazide, 20 ml of methanol, and 0.5 ml of 1N-hydrochloric acid together for 17.5 hours Let's do it. The solution was concentrated to 1/2 volume, cooled by addition of the same amount of water, and precipitated when 53 mg of 1-dimethylaminosulfonyl-2-amino-5 (6)-(α-thiocarbamylhydrazonopropyl) benzimidazole Is generated.

m / e 369

Example 26

10 ml of acetic anhydride was cooled to 0 ° C., 5 ml of formic acid (97-100%) was added slowly, then heated to 55 ° C. in a steam bath, held for 15 minutes, then quenched to 1 g (0.0035 mol) of 1-dimethylaminosulfonyl 2-Amino-5 (6) -propionylbenzimidazole is added. The slurry was added to 50 g of ice, filtered, washed with water and dried to give 1.1 g of 1-dimethylaminosulfonyl-2-formamido-5 (6) -propionyl benzimidazole.

Assay: C ₁₃ H ₁₆ N ₄ O ₄ S Theoretical: C 48.14, H 4.97, N 17.27

Molecular weight 324 found: 48.37, 5.12, 17.05

Example 27

(A) 2-amino-5 (6) -benzoyl benzimidazole

Slowly adding 300 g (1.52 mole) of 4-aminobenzophenone to a solution consisting of 250 ml of acetic anhydride and 250 ml of benzene raises the temperature to 70 ° C. The reaction mixture was stirred overnight, the precipitated product was washed with benzene, and then filtered and dried to yield 333.8 g (19.5%) of 4-acetamido benzophenone (melting point: 150-152 ° C.).

23 g (0.1 mol) of 4-acetamidobenzophenone, 50 ml of acetic anhydride and 20 ml of acetic acid are stirred together. To the benzophenone mixture 15 ml of 90% nitric acid, 10 ml of acetic acid and 0.2 g of urea are added dropwise. Maintaining the temperature at 50 ° C. during the nitration reaction and stirring the mixture at ambient temperature gives a very solid mixture, which is poured into ice and filtered to give 17.7 g (62.5 g) of 4-acetamido-3-itrobenzo Phenon is generated.

Assay: C ₁₅ N ₂ O ₄ Theory: C 63.38, H 4.26, N 9.85, O 22.51

Molecular weight 284.27 Found: 63.57, 4.03, 0.90, 22.07

10 g of 4-acetamido-3-nitrobenzophenone is added to 40 ml of sulfuric acid. The reaction temperature is stirred for 45 minutes while controlling with a water bath, and slowly poured into ice and filtered to precipitate 4-amino-3-nitro benzophenone.

Assay: C ₁₃ H ₁₀ N ₂ O ₃ Theory: C 64.46, H 4.16, N 11.56, O 19.81

Molecular weight 242.23 Found: 64.19, 4.00, 11.37, 19.72

50 g of 4-amino-3-nitrobenzophenone are hydrogenated in the presence of 945 ml of THF at a pressure of 2.74 × 10 ⁶ dyne / cm 2 at room temperature in the presence of 15 g of raninickel. After 4 hours, when 3 equivalents of hydrogen were absorbed, the catalyst was filtered off, and the filtrate was evaporated in vacuo. The remaining residue was purified by silica gel chromatography (eluent: ethyl acetate). Diaminobenzophenone is produced. 42.4 g (0.2 mol) of 3,4-diaminobenzophenone is dissolved in 100 ml of methanol and mixed in 1 L of water. 21.8 g (0.2 mol) of cyanogen bromide is slowly added while stirring to react overnight. The reaction mixture was filtered, the filtrate was neutralized with concentrated ammonium hydroxide, the precipitate was taken out, washed with water and dried in vacuo to yield 31 g (68.5%) of 2-amino-5 (5) -benzoyl benzimidazole.

Assay: C ₁₄ H ₁₁ N ₃ O Theory: C 70.87, H 4.67, N 17.71

Molecular weight 237.2 Found: 70.88, 4.60, 17.48

(B) 1-dimethylaminosulfonyl-2-amino-5 (6) -benzoylbenzimidazole

4.5 g (0.02 mole) of 2-amino-5 (6) -benzoylbenzimidazole is dissolved in 30 ml of acetone and 4 g of triethyleneamine, and 10 ml of acetone and 2.9 (0.02 mole) of dimethylsulfamoyl chloride are added dropwise. Reflux overnight. It is poured into 400 ml of water and extracted with chloroform. The extract is washed with water, dried over sodium sulfate and evaporated in vacuo. The residue was determined in ethyl acetate to yield 1.06 g of 1-dimethylaminosulfonyl-2-amino-6-benzoylbenzimidazole (melting point 206-208 ° C.).

Assay: C ₁₆ H ₁₄ N ₄ O ₃ S Theoretical: C 55.82, H 4.65, N 16.28

Molecular weight 344 found: 56.27, 4.80, 15.95

Example 28

30 g (0.126 mol) of 2-amino-5 (6) -benzoylbenzimidazole, 25 m of dimethoxyethane and 56.3 (0.13 mol) of sodium hydride (mineral oil 50%) are stirred for 1 hour. 19 g of isopropyl sulfonyl chloride and 20 ml of dimethoxyethane were added thereto, stirred at room temperature for 16 hours, refluxed for 2 hours, cooled, concentrated in vacuum, dissolved in 1,500 ml of ethyl acetate, washed with water, dried and concentrated. Make 200 ml. Cooling the solution produces a precipitate which is washed with diethyl ether to give 11.1 g of 1-isopropylsulfonyl-2-amino-6-benzoylbenzimidazole.

Assay: C ₁₇ H ₁₇ N ₃ O ₃ S Theory: C 59.46, H 4.99, N 12.24

Molecular weight 343 found: 59.20, 5.03, 12.03

Example 29

10 ml of acetic anhydride was added to 5 ml of formic acid (97 to 100%), stirred, and maintained at 50 to 55 ° C. for 15 minutes, followed by cooling to 0 ° C., and 1 g of 1-dimethylaminosulfonyl-2-amino5 (6)- Add benzoylbenzimidazole and reflux for 2 hours. The solution is poured into ice, extracted twice with chloroform, washed with sodium chloride, saturated with sodium chloride and filtered and evaporated to yield 900 mg of oil. This oil was dissolved in methanol and dried to yield 800 mg of 1-dimethylaminosulfonyl-2-formamido-5 (6) -benzoyl benzimidazole.

m / e 372

Example 30

1 g of 1-dimethylaminosulfonyl-2-amino-5 (6) -benzoyl benzimidazole, 4 ml of acetic anhydride and 4 mg of anhydrous sodium acetate are maintained at 50 ° C. for 10 minutes. After stirring, 60 ml of water was added and allowed to stand for 16 hours. Extracted three times with chloroform, washed three times with water, washed with saturated sodium chloride solution and dried to give 1 g of 1-dimethylaminosulfonyl-2-acetamido-5 (6) -benzoylbenzimidazole.

m / e 386.

Example 31

The reaction of 1.1 g of 2-amino-5 (6) -p-chlorobenzoyl benzimidazole with 573 mg of dimethyl sulfamoyl chloride as a starting material in the method of Example 28 gave 1-dimethylaminosulfonyl-2-amino- 5 (6) -p-chlorobenzoyl benzimidazole is produced.

Example 32

172 mg of 1-dimethylaminosulfonyl-2-amino-5 (6) -benzoyl benzimidazole, 100 mg of hydroxylamine hydrochloride and 20 mg of methanol were refluxed for 16 hours. The reaction mixture was concentrated to half the original volume in a steam bath, and 10 ml of buffer (pH7) was added to precipitate the precipitate. The precipitated material was filtered. Minobenzyl) Benzimidazole (melting point: 180-183 ° C.) yields 116 mg.

Assay: C ₁₆ H ₁₇ N ₅ O ₃ S Theory: C 53.47, H 4.77, N 19.49

Molecular weight 359 Found: 52.38, 5.13, 18.58

Example 33

1.7 g (0.005 mole) of 1-isopropylsulfonyl-2-amino-5 (6) -benzoylbenzimidazole, 1 g of hydroxylamine hydrochloride, and 200 ml of methanol are refluxed together for 18 hours. Concentrate to half the original volume in a steam bath, and cool by adding 100 ml of buffer (pH7) to 1.2 g of 1-isopropylsulfonyl-2-amino-5 (6)-(α-hydroxyiminobenzyl) Benzimidazole is produced.

m / e 358

Assay: C ₁₇ H ₁₈ N ₄ O ₃ S Theoretical: C 56.97, H 5.06, N 15.63

Molecular weight 358 found: 56.67, 5.34, 15.25

Example 34

1.1 g (0.003 mole) of 1-dimethylaminosulfonyl-2-amino-5 (6) -p-chlorobenzoyl benzimidazole, 600 m of hydroxylamine hydrochloride and 120 ml of methanol were used as in Example 32. Treatment with the method yields 1.5 g of 1-dimethyl aminosulfonyl-2-amino-5 (6) (α-hydroxyamino-p-chlorobenzyl) benzimidazole.

m / e 378

Example 35

530 mg following treatment of Example 23 using 688 mg (0.002 mol) of 1-dimethylaminosulfonyl-2-amino-5 (6) -benzoyl benzimidazole, 500 mg of methoxyamine hydrochloride and 80 ml of methanol 1-dimethylaminosulfonyl-2-amino-5 (6) (α-methoxyiminobenzyl) benzimidazole is produced.

Assay: C ₁₇ H ₁₉ N ₅ O ₃ S Theoretical: C 54.68, H 5.13, N 18.75

Molecular weight 373 Found: 54.66 5.06 18.92

Example 36

The oil was obtained by the Example 23 method using 1.7 g of 1-isopropylsulfonyl-2-amino-5 (6) -benzoyl imidazole, 1.2 g of methoxyamine hydrochloride, and 200 ml of methanol. The oil was treated with saturated sodium chloride, extracted with ethyl acetate, dried and extracted with benzene over several times. 1 g of 1-isopropyl sulfonyl-2-amino-5 (6)-(α-methoxyiminobenzyl) benz Imidazole is produced.

Assay: C ₁₈ H ₂₀ N ₄ O ₃ S Theoretic: C 58.05, H 5.41, N 15.04

Molecular weight 372 Found: 57.98, 5.72, 14.99

Example 37

718 mg (0.002 mol) of 1-dimethylaminosulfonyl-2-amino-5 (6)-(α-hydroxyiminobenzyl) benzimidazole was added to 15 ml of ethanol (95%) and stirred, and 120 mg (0.0022 mol) ) Sodium methoxide is added and 552 mg (0.0054 mole) of ethyl iodide is added. After refluxing for 2.5 hours, it is cooled and concentrated to 1/2 of the original volume. The solution was poured into water, extracted twice with chloroform, washed twice with saturated sodium chloride, and then dried and filtered to give 1-dimethyl-amino sulfonyl-2-amino-5 (6)-(α-ethoxyiminobenzyl) benzimidazole. This produces 227mg.

Assay: C ₁₈ H ₂₁ N ₅ O ₃ S Theoretical: C 55.80, H 5.46, N 18.08

Molecular weight 387 Found: 56.03, 5.3, 18.27

Example 38

718 mg (0.002 mol) of 1-dimethylaminosulfonyl-2-amino-5 (6)-(α-hydroxyiminobenzyl) benzimidazole, 15 ml of methanol, 120 mg (0.00354 mol) of sodium methoxide and 600 mg of 248 mg of 1-dimethylaminosulfonyl-2-amino-5 (6)-(α-propoxyiminobenzyl) benzimidazole as white crystals produced 248 mg of 1-dodopropane by the method of Example 37. do.

Assay: C ₁₉ H ₂₃ N ₅ O ₃ S Theoretical: C 56.84, H 5.77, N 17.44

Molecular weight 401 found: 56.63, 5.54, 17.60

Example 39

172 mg (0.5 mmol) of 1-dimethylaminosulfonyl-2-amino-5 (6) -benzoyl benzimidazole, 230 mg (1.45 mmol) of benzyloxyamine hydrochloride and 200 ml of methanol are refluxed for 19.5 hours. Treatment of the solution by the method of Example 32 yields 161 mg of 1-dimethylaminosulfonyl-2-amino-5 (6)-(α-benzyloxyiminobenzyl) benzimidazole.

Assay: C ₁₃ H ₂₃ N ₅ O ₃ S Theoretical: C 61.45, H 5.16, N 15.58

Molecular weight 449 found: 61.51, 5.20, 15.37

Example 40

54 mg (0.001 mol) of sodium methoxide in 359 mg (0.001 mol) of 1-dimethylaminosulfonyl-2-amino-5 (6)-(α-hydroxyiminobenzyl) benzimidazole and 4.4 ml of dimethylformamide After stirring, 102 mg (0.001 mol) of acetic anhydride was added and stirred for 5 minutes. To this solution is added 26.5 ml of water and 25 ml of buffer (pH 7). The solution was stirred for 1 hour and filtered to yield 320 mg of 1-dimethylaminosulfonyl-2-amino-5 (6)-(α-acetoxyiminobenzyl) benzimidazole (melting point: 137 to 139 ° C).

Assay: C ₁₈ H ₁₉ N ₅ O ₄ S Theoretical: C 53.85, H 4.77, N 17.45

Molecular weight 401 found: 53.58, 4.59, 17.08

Example 41

1 g (0.003 mole) of 1-isopropylsulfonyl-2-amino-5 (6)-(α-hydroxyiminobenzyl) benzimidazole and 162 mg (0.003 mole) of sodium methoxide and 10 ml of dimethylformamide Treatment of 0.3 ml of acetic anhydride according to the method of Example 40 yields 900 mg of 1-isopropylsulfonyl-2-amino-5 (6)-(α-acetoxyiminobenzyl) -benzimidazole.

Assay: C ₁₉ H ₂₀ N ₄ O ₄ S Theoretical: c 56.99, H 5.03, N 13.99

Molecular weight 400 found: 57.20, 5.24, 13.86

Example 42

181 mg of 1-dimethylaminosulfonyl-2-amino-5 (6)-(α-aminohydroxyiminobenzyl) benzimidazole, 2 ml of pyridine, and 2 ml of acetic anhydride are mixed and allowed to stand at room temperature for 17.5 hours. The solution was evaporated to dryness, extracted with methanol and evaporated to yield 132 mg of 1-dimethylaminosulfonyl-2-acetamido-5 (6)-(α-acetoxyiminobenzyl) benzimidazole (melting point: 162 to 165 ° C). ) Will generate.

Analyzes: C ₂₉ H ₂₁ N ₅ O ₅ S Theoretical: C 54.17, H 4.77, N 15.79

Molecular weight 443 found: 54.03, 4.89, 15.85

Example 43

359 mg (0.001 mol) of 1-dimethylaminosulfonyl-2-amino-5 (6)-(α-hydroxyaminobenzyl) benzimidazole with 4.4 ml of dimethylformamide and 54 mg (0.001 mol) of sodium methoxide And 130 mg of propionic anhydride were treated by the method of Example 40 to give 1-dimethylaminosulfonyl-2-amino-5 (6)-(α-propionyloxyiminobenzyl) benzimidazole.

m / e 415.

Example 43A

359 mg (0.001 mol) of 1-dimethylaminosulfonyl-2-amino-5 (6)-(α-hydroxyiminobenzyl) benzimidazole, 4.4 ml of dimethylformamide, 54 mg of sodium methoxide and 158 mg (0.001) Treatment with the method of Example 40 using mol) butyric anhydride yields 342 mg of 1-dimethylaminosulfonyl-2-amino-5 (6)-(α-butyryloxyiminobenzyl) benzimidazole.

Assay: C ₂₀ H ₂₃ N ₅ O ₄ S Theoretic: C 55.93, H 5.40, N 16.31

Molecular weight 429 found: 54.05, 5.21, 17.13

Example 44

539 mg (0.0015 mol) of 1-dimethylaminosulfonyl-2-amino-5 (6)-(α-hydroxybenzyl) benzimidazole, 6.6 ml of dimethylformamide and 51 mg (0.015 mol) of sodium methoxide Treatment of 339 mg (0.0015 mol) of benzoic anhydride by the method of Example 40 yields 600 mg of 1-dimethylaminosulfonyl-2-amino-5 (6)-(α-benzoyloxyiminobenzyl) benzimidazole.

m / e 463.

Example 45

359 mg (0.001 mol) of 1-dimethylaminosulfonyl-2-amino-5 (6)-(α-hydroxyiminobenzyl) benzimidazole was added 4 ml of dimethylformamide and 63 mg (0.0012 mol) of sodium methoxide. 100 mg (0.0011 mol) of methoxy carbonyl chloride and 0.5 ml of dimethylformamide were added again and stirred for 5 minutes, 40 ml of buffer solution (pH 7) was added, stirred again for 5 minutes, filtered, washed with water and dried. 1-dimethylaminosulfonyl-2-amino-5 (6)-(α-methoxy carbonyliminobenzyl) -benzimidazole is produced.

m / e 417.

Example 46

172 mg of 1-dimethylaminosulfonyl-2-amino-5 (6) -benzoylbenzimidazole, 100 mg of thiosemicarbazide, 0.5 ml of 1N-hydrochloric acid and 20 ml of methanol were refluxed for 16 hours and cooled to thiosemicarba John precipitates and the amount and composition is 94 mg of 1-dimethylaminosulfonyl-2-amino-5 (6) -thiocarbamylhydrazonobenzyl benzimidazole.

m / e 417.

Example 47

To 300 ml (0.0093 mol) boiling ethanol is added 3.2 g of 1-dimethylaminosulfonyl-2-amino-5 (6) -benzoylbenzimidazole and 1 g (0.0096 mol) of ethoxycarbonyl hydrazine.

The mixture is heated for 4 hours, 1 ml of concentrated hydrochloric acid is added, and heated again for 10 hours. After the solvent was removed, 300 ml of water was added thereto, and the mixture was left to stand for 19 hours, extracted with ethyl acetate, dried, and concentrated. Then, 1.7 g of 1-dimethylaminosulfonyl-2-amino-5 (6)-(α-ethoxycarbonylhydrazo) was added. Nobenzyl) benzimidazole is produced as a foam.

Assay: C ₁₉ H ₂₂ N ₆ O ₄ S Theoretic: C 53.01, H 5.15, N 19.52

Molecular weight 430 found: 52.82, 5.51, 18.44

Example 48

3 g (0.00875 moles) of 1-isopropylsulfonyl-2-amino-5 (6) -benzoylbenzimidazole, 300 ml of anhydrous ethanol, 1 g (0.0096 moles) of ethoxycarbonylhydrazine and 1 ml (0.01 moles) of Treatment with the method of Example 47 using concentrated hydrochloric acid yields 2.4 g of 1-isopropylsulfonyl-2-amino-5 (6)-(α-ethoxycarbonylhydrazonobenzyl) benzimidazole. .

m / e 429, 357, 343

Assay: C ₂₀ H ₂₃ N ₅ O ₄ S Theoretic: C 55.93, H 5.40, N 16.31

Molecular weight 429 found: 55.96, 5.10, 16.57

Example 49

1.7 g (0.00 mol) of 1-isopropylsulfonyl-2-amino-5 (6) -benzoylbenzimidazole, 200 ml of methanol, 1.1 g of carboxymethoxyamine hemihydrochloride and 0.3 ml (0.003 mol) of Treatment of concentrated hydrochloric acid by the method of Example 47 yields 2 g of 1-isopropylsulfonyl-2-amino-5 (6)-(α-carboxymethoxyiminobenzyl) benzimidazole.

pka 6.91 (66% dimethylformamide / water)

Example 50

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

10.3 g (0.05 mole) of 3-nitro-4-acetamidobenzonitrile, 3.5 g of sodium azide, 3.9 g of ammonium chloride and 100 ml of dimethylformamide were refluxed for 16 hours. After cooling, put into 500ml of 1N hydrochloric acid and dilute with 300ml of water. Quantitative and qualitative yellow crystals show that 10 g (81%) of 5- (3-nitro-4-acetamidophenyl) tetrazole.

Melting Point: 210 to 213 ° C (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 and stirred uniformly, 30 ml of methyl iodide is added and 20 ml of methyl iodide is added after 12 hours at room temperature. The reaction was further selected for 4 hours to select 20 g (59%) of isomers of 1 (2) -methyl-5- (3-nitro-4-acetamidophenyl) tetrazole.

Assay: C ₁₀ H ₁₀ N ₆ O ₃ Theoretic: C 45.80, H 3.84, N 32.05

Molecular weight 262 found: 45.64, 3.84, 32.18

(C) 1 (2) -methyl-5- (3-nitro-4-aminophenyl) tetrazole

2 g of 1 (2) -methyl-5- (3-nitro-4-acetamidophenyl) tetrazole is added to 20 ml of concentrated sulfuric acid at room temperature. Tetrasol dissolves gradually. After the melt was stirred for about 2 hours and the acid mixture was carefully added to 200 ml of cold water, 1.6 g (95 ° C) of 1 (2) -methyl-5- (3-nitro-4-amino) tetrazole %)

Assay: C ₈ H ₈ N ₂ O ₂ Theory: C 43.64, H 3.66, N 38.17

Molecular weight 220 found: 43.37, 3.70, 37.89

(D) 1 (2) -methyl-5 (3,4-diaminophenyl) tetazole

14 g of 1 (2) -methyl-5- (3-nitro-4-aminophenyl) tetrazole was prepared using 4.13 × 10 ⁶ dyne / cm 2 using 1 g of palladium-carbon in 135 ml of ethyl acetate and 350 ml of anhydrous ethanol. Hydrogenation under pressure absorbs three equivalents of hydrogen after two hours. The catalyst was filtered off and the filtrate was evaporated in vacuo resulting in 12 g (98%) of 1 (2) -methyl-5- (3,4 diaminophenyl) tetrazole.

Assay: C ₈ H ₁₀ N ₆ Theoretic: C 50.52, H 5.30, N 44.18

Molecular weight 190 found: 50.79, 5.57, 43.95

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

Slurry consisting of 3.2 g (0.03 mole) of cyanogen bromide with 5.7 g (0.03 mole) of 1 (2) -methyl-5- (3,4-diaminophenyl) tetazole, 300 ml of water and 30 ml of methanol The mixture was stirred for 12 hours and filtered. The filtrate was neutralized with potassium carbonate and the precipitate was taken to give 5.7 g (88%) of 1 (2) -methyl-5- (2-aminobenzimidazol-5 (6) -yl) tetrazole.

Assay: C ₉ H ₉ N ₇ Theoretic: C 50.23, H 4.22, N 45.56

Molecular weight 215 found: 49.56, 4.34, 44.06

(F) Triethylamine of 1-dimethylaminosulfonyl-2-amino-5 (6)-[1 (2) -methyltetrazol-5-yl] benzimidazole and 1 g of dimethylsulfamoyl chloride for 18 hours. Reflux. After cooling the unreacted starting was filtered off, and the filtrate was evaporated to treat the oily residue with methanol. 300 mg of 1-dimethylaminosulfonyl-2-amino-5 (6)-[1 (2) -methyltetrazole- 5-yl] benzimidazole is produced.

Assay: C ₁₁ H ₁₄ N ₈ O ₂ S Theoretical: C 40.99, H 4.38, N 34.76

Molecular weight 322 found: 40.72, 4.38, 34.51

The following intermediates and final products were made by the method of Example 50. Only one isomer is produced when isopropyl iodide is used in the alkylation reaction of the tetrazole site.

Example 51

(A) 1-isopropyl-5- (3-nitro-4-aminophenyl) tetrazole

Melting Point: 126-128 ° C Yield 71% Theoretical Value: C 48.38, H 4.87, N 33.85

Assay: C ₁₀ H ₁₂ N ₆ O ₂ Molecular weight: 200 Found: 48.19, 4.93, 33.61

(B) 1-isopropyl-5- (3,4-diaminophenyl) tetrazole

Yield 70% Theoretical Value: C 55.03, H 6.47, N 38.50

Anal: C ₁₀ H ₁₄ N ₆ found: 55.23, 6.27, 37.73

Molecular Weight: 218

(C) 1-isopropyl-5- [2-aminobenzimidazol-5 (6) -yl] tetrazol

Melting Point: 232 ~ 233 ° C Yield 7.3g (86%) Theoretical Value: C 54.31, H 5.39, N 40.30

Assay: C ₁₁ H ₁₃ N ₇ Molecular weight: 243 Found: 54.56, 5.54, 40.53

(D) 1-dimethylaminosulfonyl-2-amino-5 (6)-(1-isopropyltetrazol-5-yl) benzimidazole

Melting point: 211 to 213 ° C Molecular weight: 350 Theoretical value: C 44.56, H 5.18, N 31.98

Anal: C ₁₃ H ₁₈ N ₈ O ₂ S Found: 44.83, 5.33, 31.77

Example 52

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

(A) 3 g of 1-dimethylaminosulfonyl-2-amino-5 (6) -benzimidazole carboxylic acid hydrazide ethyl-1-dimethylaminosulfonyl-2-amino-5 (60-benzimidazole carboxylate 59 ml of methanol and 6 ml of hydrazine hydrate were refluxed for about 100 hours.

The hydrazide product crystallizes in solution during the reaction and filtration of the hot reaction mixture yields 200 mg of 1-dimethylaminosulfonyl-2-amino-5-benzimidazole carboxylic acid hydrazide (melting point: 229-230 ° C.). .

Assay: C ₁₀ H ₁₄ N ₆ O ₃ S Theoretic: C 40.30, H 4.70, N 28.20

Molecular weight: 298 Found: 40.21, 4.54, 28.33

The solid obtained by cooling the filtrate can be seen by filtration to confirm that the solid is an isomeric mixture of acid hydrides. Continued concentration to complete crystallization results in 350 mg of 1-dimethylaminosulfonyl-2-amino-6-benzimidazole carboxylic acid high. Dragged hydrate (melting point: 205-206 ° C.) is produced.

Assay: C ₁₀ H ₁₄ N ₆ O ₃ S Theory: C 37.97, H 5.06, N 26.58

Molecular weight: 316 found: 38.40, 4.41, 26.15

(B) 1-dimethylaminosulfonyl-2- [ethoxymethyleneamino-5 (60- (1,3,4, -oxadiazol-2-yl)] benzimidazole

3 g (0.01 mole) of 1-dimethylaminosulfonyl-2-amino-5 (6) -benzimidazole carboxylic acid hydrazide and 100 ml of ethyl ortho formate are refluxed for 24 hours using a Dean-Stark trap. The reaction mixture is evaporated to dryness and the residue is dissolved in ethyl acetate. The product crystallizes by concentration and cooling. 580 mg of 1-dimethylaminosulfonyl-2- (ethoxymethyleneamino) -5 (6)-(1,3,4-oxadiazol-2-yl) benzimidazole can be obtained.

Assay: C ₁₄ H ₁₆ N ₆ O ₄ S Theoretic: C 46.15, H 4.40, N 23.08

Molecular weight: 364 Actual value: 46.19, 4.38, 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 in 1 ml of 1N-hydrochloric acid at room temperature Stir for time. The reaction mixture was filtered to give 230 mg of 1-dimethylaminosulfonyl-2-amino-5 (60- (1,3,4-oxadiazol-2-yl) benzimidazole hydrochloride (melting point: 200 ° C decomposition). Create

Assay: C ₁₁ H ₁₂ N ₆ O ₃ SHCl Theory: C 38.32, H 3.80, N 24.38

Molecular weight: 344.5 Found: 42.61, 3.92, 27.26

The remaining solution of (C) was treated with sodium carbonate until it became basic to litmus, and the resultant precipitate was filtered to give 1-dimethylaminosulfonyl-2-amino-5 (6) having a melting point of 230 to 231 캜 (decomposition). 120 mg of-(1,3,4-oxadiazol-2-yl) benzimidazole are obtained.

Assay: C ₁₁ H ₁₂ N ₆ O ₃ S Theoretical: C 42.85, H 4.19, N 27.03

Molecular weight: 308 found 42.61, 3.92, 27.26

Example 53

475 g of 2-amino-5 (6) 0-benzoylbenzimidazole, 2.5 moles of sodium hydride and 365 g of cyclohexylsulfonyl clyde were treated by the method of Example 27 and 120 g of 1-cyclohexylsulfonyl-2 -Amino-6-benzoylbenzimidazole (melting point: decomposition from 210 ° to 123 ° C.) is produced.

Assay: C ₂₀ H ₂₁ N ₃ O ₃ S Theoretical: C 62.64, H 5.52, N 10.96

Molecular weight: 383 Found: 62.43, 5.27, 10.51

Example 54

26.4 g (1.1 mole) of sodium hydride, 260 g (1.1 mole) of 2-amino-5 (6) -benzoyl benzimidazole, and 200 g of thiophene sulfonylchloride were prepared by the method of Example 27. Thien-2-yl sulfonyl) -2-amino-5 (6) -benzoyl benzimidazole is produced. m / ℓ 351

The compound of formula (1) exhibits a wide range of antiviral effects.

The compound of formula (1), which is a compound of the present invention, is Echovirus, Mengo, Coxsackie (A9, 21, 5), polio (Tape I, II, III) or Renovirus (25 species), as well as Anabo and Mathielan. It has a strong effect on the growth inhibition of influenza viruses, including influenza strains such as B, Massachusetts B, Hong Kong A, Pr-8a and Taylor (Taipei A, B). The ability of compounds within the range of formula (I) to inhibit various viral growths in vitro is similar to the method described by Siminoff in Applied Mierobiology, 9 (1), 66-72 (1961). You can easily experiment using the method. The above effects are confirmed by the following test methods.

[Test Methods]

1 ml of FBS (fetal bovine serum), penicillin (150 units) and streptomycin (5% inactivated) in African monkey kidney cells (BSC-1) or HeLa cells (5-3) maintained at 37 ° C in a 25cc bow cone flask 150 μg / ml) in medium 199. Once the supernatant layer is formed, remove the supernatant medium and add 0.3 ml of the appropriate virus dilution (eco, mengo, coxsackie, polio or rhinovirus) into each flask. The virus-infected cells were adsorbed for 1 hour at room temperature and 100,50,25,12,6 in 1 part of medium having twice the strength containing 1 part of Iongar No. 2, FBS, penicillin and streptomycin. Add 3,0 μg / ml of this compound. The effect of this compound is measured by comparison with the medium which this compound is not added. Sulfonylbenzimidazole compounds are made from a dimethylsulfoxide diluent having a concentration of 104 μg / ml. Folio, Coxsackie, Echo, and Mengo virus flasks were maintained at 37 ° C. for 72 hours and linovirus flasks were incubated at 32 ° C. for 120 hours. Spots appear in areas where viruses infect and grow in cells. 10% formalin and 2% acetate sodium solution are added to each flask to inactivate the virus and fix the cells to the surface of the flask. The number of irregularly sized virus spots is counted after staining the surrounding cells with a crystal bioretro, and the number is measured according to the amount of the present compound compared with the number of the control group of each drug concentration. The activity of the test compound is expressed as a percentage reduction (%) or inhibition rate (%). The concentration of the compound is determined as the amount of 50% inhibition. This 50% inhibitory effect is represented by I 50.

These results are referred to in terms of poliovirus type I inhibition because poliovirus type I is easy to grow and consistent results are obtained. However, the activity of the compounds of the formula (I) was found to be Coxsakie (A9, A21, B5), echo virus (strain _1-4 ), mengo, rhinovirus (25 strains) and polio ( polio: Identification tests are also performed for other viruses such as type I, II, and III).

The experimental results for the various sulfonyl benzimidazole compounds are summarized in the following table (I), where column 1 is the previous example number of compound synthesis, and column 2 is the 5 (6) -position of the corresponding benzimidazole. And columns 3-10 show percent virus decrement at drug dilution multiples from 0.75 to 100 mcg / ml.

TABLE 1

Sulfonylbenzimidas were either pure or mixtures of isomers, all of which had viral growth inhibitory effects, and the 6-isomer generally outperformed the 5-isomer.

Compounds of formula (I) can inhibit the growth of several viruses when added to the medium in which the virus is growing, so compounds of formula (I) can be made into aqueous solutions (especially with surfactants). , Tinoviruses and other virus contaminated surfaces (medical containers, food containers, etc.).

In addition, the compound of formula (1) may be orally administered to warm-blooded animals in an amount of 1 to 300 mg / kg per body animal, and if necessary, periodic administration is also possible. In this case, it is usually good to administer every four to six hours.

The compound of formula (1) may be mixed with an excipient so as to be suitable for administration, and in the case of oral administration, lactose, sucrose, starch, cellulose, active, magnesium stearate, magnesium oxide, calcium sulfate salt, sodium benzoate, stearic acid, etc. It may be formulated with the same carrier or diluent, and may be in the form of tablets, capsules, or parenteral administration, or may be mixed with a liquid and used as a nasal drops or sprays for administration.

Claims (1)

A compound of formula (II) is reacted with a compound of formula (III) to prepare a compound of formula (I) wherein R ₁ is hydrogen and Z is oxygen, optionally substituted amine, thiosemi carbazide, semi React with carbazide, hydrazine, substituted hydrazine, 1,3-propane dithiol or ethanedithiol to form a compound in which Z is not oxygen or C _1-4 acyloxyimino, and alkylate a compound in which Z is hydroxyimino A compound of formula (I) is prepared by preparing and acylating a compound in which Z is C _1-4 alkoxyimino to prepare a compound in which Z is C _1-4 acyloxyimino or R ₁ is C _1-4 acyl. How to.

Wherein R is C _1-4 alkyl, C _5-7 cycloalkyl, thienyl, phenyl or —NR ₃ R ₄ , wherein R ₃ , R ₄ are independently C _1-3 alkyl. R ₁ is hydrogen or C _1-4 acyl, R ₂ is hydrogen, C _1-4 alkyl, phenyl, halophenyl, 1- (C _1-3 alkyl) tetrazol-5-yl, 1,3,4-oxa oxadiazole-2-yl, or C _3-6 cycloalkyl, Z is oxygen, hydroxyimino, methoxycarbonyl oksiyi Mino, C _1-4 alkoxyimino, C _1-4 acyl oksiyi Mino, benzyl oksiyi Mino, benzoyl Oxyimino, hydrazono, thiocarbamylhydrazono, carboxymethoxyimino, methoxycarbonylhydrazono, ethoxycarbonylhydrazono, carbamylhydrazono, 1,3-dithiolane-2- 1,3-dithiane-2-yl,

Must be in position 5 or 6, where n is 0 or 1, provided that R ₂ is 1- (C _1-3 alkyl) tetrazol-5-yl or 1,3,4-oxadiazole-2 N must be zero for -days.