KR800001218B1 - Process for thiazolinil ketobenzimidazole - Google Patents

Abstract

Title compds. [I; R = H; R1 = C1-3 alky1, thieny1 or pheny1; Z = hydroxyimino, thiocarbamy1hydrazono, α-methoxycarbonylmethoxyimino, or α-hydroxycarbonylimino, R1-(C=Z)m in the 5- or 6- position; m = 1; z1 = 0;X = chloro or bromo were manufd. Thus, II was reacted with haloethylisothiocyanate of compd. (IV) in presence of base and solvent to give I(R = H ; Z = O), which was hydrated with substituted amine or thiosemicarbazide to give I.

Description

Method for preparing thiazolinyl kerobenzamidazole and derivatives thereof

The present invention relates to a process for preparing a thiazolinyl ketobenzimidazole compound of formula (I) which is useful for inhibiting the growth of a virus.

In the above structural formula

R is hydrogen

R ₁ is alkyl having 1 to 3 carbons, thienyl or phenyl

Z is hydroxyimino, α-methoxycarbonylmethoxyimino, α-hydroxycarbonylmethoxyimino or thiocarbamyl hydrazono,

은 5 또는 6위치에 있으며,

Is in the 5 or 6 position,

m is 1.

The upper respiratory disease caused by the virus is very widespread and is reported to reach almost billions of years in the United States alone each year. A study conducted in the UK (Tyrell and Byron Lancet 1,76 1966) indicated that 74% of people with colds were infected with the nasal cold virus. Since more than 80 nasal cold viruses are known, the development of substantial nasal cold virus waxes is not easy, so chemotherapy has emerged as a more desirable treatment.

The ability of chemical compounds to inhibit the growth of viruses was readily found by in vitro testing using a viral anti-spot test similar to that described by Applied Microbiology 9 (1) 66 (1961) by Siminov.

Thiazolinyl benzimidazole compounds are disclosed in the following documents.

US Patent No. 3,749,717 discloses 1-thiazolinyl-2- (heterocyclic) benzimidazole useful as an antiparasitic and anti-inflammatory agent, and US Pat. No. 3,825,537 discloses 1-thiazolinyl-2- useful as an antiparasitic and anti-inflammatory agent. Aminobenzimidazoles have been published, and No. 3,833,574 discloses a process for preparing 1-thiazolinyl benzimidazolin-2-ones having anti-inflammatory action.

Derwent, 26199w / 16 discloses 1-thiazolinyl-2-phenyl benzimidazole useful as an antiparasitic agent and no literature on the antiviral action of thiazolinyl benzimidazole has been published.

The compounds of the present invention are highly effective at inhibiting the growth of viruses, particularly nasal cold virus polio virus, cocksuckie virus, echovirus, mengo virus, and influenza.

The process of the present invention provides the following formula (II) compound in the presence of a base such as sodium hydride, sodium methoxide, or potassium t-butoxide and a solvent such as tetrahydrofuran, toluene, or dimethoxyethane. CH ₂ ) ₂ -NCS (IV) is reacted with haloethylisothiocyanate to obtain a compound of formula (I) wherein R is hydrogen and Z is oxygen, and the compound is substituted with a substituted amine or thiosemicarbazide. Optionally reacting to prepare a compound of formula (I) wherein Z is hydroxyimino, thiocarbamylhydrazone, α-methoxycarbonylmethoxyimino, or α-hydroxycarbonylmethoxy imino.

In the above structural formula

Z 'is oxygen,

R ¹ and m are as described above,

X is chloro or bromo.

The present invention relates to a method for preparing a thiazolinyl benzimidazole compound effective in inhibiting the growth of viruses such as nasal cold virus, polio virus, cocksuckie virus, echovirus, mengo virus and influenza in mammals. .

Compounds useful in the preparation of the present invention include salts (III) of tautomeric benzimidazole compounds represented by the following formula (II) with haloethyl isothiocyanates of formula (IV), i.e., X- (CH ₂ ) ₂ -NCS ( Optionally substituted with a methyl group on the carbon chain, wherein R ₁ , Z and m are as described above and X is chloro or bromo) to react with the compound of formula (V) wherein R is hydrogen and Z is oxygen It is prepared by obtaining the compound of formula (I).

의 치환체를 갖는 벤즈이미다졸 반응물은 상응하는 호변이성체를 가지며 이는 평형상태에 있고 여기에서는 치환체가 6위치에 선택적으로 존재한다. 이성체 혼합물은 5(6)으로 선택위치에 번호를 붙이므로서 지시될 수 있다. 이러한 호변 이성체의 결과로서 5(6)-치환된 벤즈이미다졸염(Ⅲ)을 할로에틸 이소티오시아네이트(Ⅳ)와 반응시키면 5(6)-치환된 화합물로 명명되는 5-또는 6-치환된 티아졸리닐 벤즈이미다졸(Ⅴ)의 이성체 혼합물을 생성한다. 다음의 정의는 본 명세서를 통해 사용된 여러가지 용어에 관한 것이다. “탄소수 1내지 3의 알킬”이란 용어는 메틸, 에틸, 프로필 및 이소프로필과 같이 1내지 3개의 탄소수를 갖는 직쇄 또는 측쇄의 지방족 기이다. 탄소수 1내지 3의 알킬기는 “탄소수 1내지 2의 알킬”기의 정의에 포함된다.The term "tautomer benzimidazole" refers to a benzimidazole compound of formula (II) in which a nitrogen atom can be substituted with a hydrogen atom. Nitrogen atom is not substituted and is located at 5 position of benzene

Benzimidazole reactants with substituents of have the corresponding tautomers, which are in equilibrium where the substituents are optionally present at position 6. Isomer mixtures can be indicated by numbering the selection positions with 5 (6). As a result of these tautomers, the reaction of 5 (6) -substituted benzimidazole salts (III) with haloethyl isothiocyanate (IV) results in 5- or 6-substituted compounds, termed 5 (6) -substituted compounds. To yield an isomeric mixture of thiazolinyl benzimidazole (V). The following definitions relate to various terms used throughout this specification. The term “alkyl having 1 to 3 carbons” is a straight or branched aliphatic group having 1 to 3 carbon atoms, such as methyl, ethyl, propyl and isopropyl. Alkyl groups of 1 to 3 carbon atoms are included in the definition of “alkyl of 1 to 2 carbon atoms”.

The term "alkyl amine having 1 to 4 carbon atoms" refers to an aliphatic amine having 1 to 4 carbon atoms described above. Methoxy amine hydrochloride is commercially available and other hydrosylamine derivatives are alkylated with acetone oxime with alkyl halides of 1 to 4 carbon atoms, followed by acid hydrolysis or alkylation of N-hydroxyphthalamide followed by gahydrazine decomposition, Obtained by acid hydrolysis of benzhydrooxamic acid after alkylation.

The term “thiazolinyl” or “thiazolin-2-yl” relates to the N ¹ moiety of formula (I), which refers to the 4,5-dihydrothiazole group attached at position 2, which is 4 and / or 5 It may also have a methyl substituent in the-position.

The compound of formula (V) (formula (I) wherein R is hydrogen and Z is oxygen) may be selected from benzimidazole reactants (II), which are suitably substituted with metal hydrides such as sodium hydride or potassium hydride, metal amides such as sodium amide; It is prepared by converting to salt (III) thereof by treating with a base such as an alkali metal alkoxide such as sodium methoxide, potassium ethoxide or sodium butoxide. The formation of anions can be carried out by aromatic hydrocarbons such as benzene, toluene or xylene; In various aprotic solvents such as ethyl ether, glyme or ether such as tetrahydrofuran at temperatures between about 0 ° C. and 150 ° C. over 1 to 24 hours. This requires a slight excess of base so the molar ratio of benzimidazole reactant to base is about 1: 1 to 1: 2.

Benzimidazole anion (III) reacts with aliphatic haloethyl isothiocyanate (IV) to form thiourea intermediates in situ, which are intramolecular alkylated on sulfur atoms to form 1-thiazolinyl benzimide of formula (V). Produces a dazole. The molar ratio of benzimidazole reactant (II) to haloethyl isothiocyanate (IV) is 1: 1 to 1: 1.5 and the reaction time is from 1 to 24 hours at temperatures between 25 ° C and 150 ° C. The method and conditions for preparing 1-thiazolinyl benzimidazole are similar to those described in US Pat. Nos. 3,749,717 and 3,825,537.

Thiazolinyl benzimidazole products are separated by conventional methods such as filtration and concentration of the filtrate to induce crystallization. The reaction mixture is also evaporated to dryness and the residue is separated by treatment with a suitable solvent such as acetone or methanol to remove insoluble matters. The solution containing the product is concentrated to crystallize the product or evaporate to give a secondary residue which is then recrystallized in a solvent such as methanol. Benzimidazole compounds are recovered by filtration or centrifugation.

The reaction of tautomer anions (III) with haloethylisothiocyanates generally provides a 1: 1 mixture of 5 (6) -isomers of the thiazolinyl benzimidazole product. 5 (6) -isomers are separated by fractional crystallization or column chromatography. Usually the 6-isomer is crystallized first in the solution of the mixture. Each isomer except for the 5 (6) benzoyl or 5 (6) -substituted-benzoyl compounds or derivatives thereof is evident by PMR in the phenyl proton range (7.0 to 8.3 ppm).

The nitrogen derivative of the keto benzimidazole compound is represented by the structural formula (I) in which Z is a nitrogen functional group bonded to the carbon atom of the original carbonyl group. These compounds are usually prepared by the appropriate 1-thiazolinyl-2-substituted-5 (6) -keto benzimidazoles with alkoxyamines, carboxymethoxylamines or thiosemi carbazides or derivatives thereof having 1 to 4 hydroxylamine carbon atoms. It is prepared by reaction in the method of. When the carbonyl (keto) group is slowly reacted with the carbonyl reagent, the keto compound can be activated by protonation under acidic conditions, and protonation easily forms a carbon-nitrogen double bond.

에서 질소관능기 Z는 아래와 같이 유도된 것으로서 카보닐 시약에 따라 명명된다.

The nitrogen functional group Z in is derived as follows and is named according to the carbonyl reagent.

Most preferred compounds are nitrogen derivatives wherein Z is hydroxyimino. In such compounds, the 6-isomer is preferred to the 5-isomer.

It will be appreciated by those skilled in the art that advantageous chemical reactions can be carried out at any stage of product synthesis. For example, the benzimidazole reactant may be chemically modified to provide the necessary substituents and reacted with the appropriate haloethyl isothiocyanate to obtain the thiazolinyl benzimidazole product.

Optionally, the 1-thiazolinyl benzimidazole compound is prepared initially and then chemically modified to give the final product. Inserting the thiazolinyl moiety into the benzimidazole reactant requires reaction with a base and the benzimidazole reactant preferably has a substituent that is not attacked by the base.

For example, in the above compound where Z is a nitrogen function (slightly unstable to base), the acyl or nitrogen function is preferably introduced after the thiazolin portion is formed.

Keto benzimidazole reactants wherein R ₁ is other than hydrogen can be prepared from benzimidazole, a suitable keto 0-phenylene diamine compound by methods well known in the art.

For example, published Belgian Patent Application No. 93791 discloses the preparation of keto-0-phenylene diamines of the following structural formula.

In the above structural formula

R ₁ is lower alkyl, or phenyl.

This preparation method is a 4-halo-3 prepared by a Friedel-Crafts reaction in which (1) 4-halo-4-nitrobenzoyl chloride is reacted with a suitable hydrocarbon or (2) aromatic halide is reacted with a suitable acid chloride. -Reduction and ammonolysis of nitrophenyl ketones. This method produces keto 0-phenylenediamine, which is itienyl in the compound. Optionally, the keto benzimidazole reactants can be prepared from acetanilide by using Friedel-Craft acylation using an appropriate derivative of alkanoic acid, phenyl acetic acid or benzoic acid having 2 to 8 carbon atoms.

2-nitro-4-keto acetanilide was made by nitrifying the resulting 4-keto acetanilide, and acetanilide was hydrolyzed to prepare 2-nitro-4-keto aniline. Catalytic hydrogenation of nitroaniline yields 4-keto-0-phenylenediamine which is reacted with anogen bromide to yield 2-amino-5 (6) -keto benzimidazole. 2-aminobenzimidazole compounds are prepared by ring-cloning 0-phenylene diamine with cyanorene bromide according to the method of Burl et al. Reference: Biol. ChemJ. 32, 1101 (1938) Various preparations of benzimidazole have also been published in the literature.

See Weissberg, “The Chemistry of Heterocyclic Compounds Imidazole and Its Derivatives” (Interscience Publisher Co ,. New York, 1953).

The haloethyl isothiocyanate reactant of formula (IV) can be prepared from its corresponding haloalkylamine (VI) and thiophosgene.

Another method for the preparation of haloethylisothiocyanate (IV) is shown in Methoden Der Organischen Chemie, Vol. 9 (G. Thieme Verlay Stuttgart, 1955). Examples of haloethyl isothiocyanate used here are as follows.

SCN (CH ₂ ) ₂ Br and SCN (CH ₂ ) ₂ Cl

이고 R₁은 탄소수 1내지 3의 알킬 또는 페닐이다.Preferred compounds used in the preparation of the invention are 1- (thiazolin-2-yl) -amino-5 (6) -keto-benzimidazoles wherein the carbonyl group

And R ₁ is alkyl or phenyl having 1 to 3 carbon atoms.

Examples of preferred thiazolinyl ketobenzimidazoles falling within the scope of structural formula (I) are as follows.

1- (thiazolin-2-yl) -2-amino-5 (6)-(α-hydroxyiminobenzyl) benzimidazole.

Compounds of formula (I) have a wide range of antiviral actions. The compounds of the present invention are effective in suppressing the growth of echovirus, mengo, coxsackie (A9, A21, B5) polio (type I, II, III) or nasal cold virus (strain 25) as well as En Arbor, Maryland B. It also has inhibitory effects against various types of influenza viruses such as Massachusetts B, Hong Kong A, Pr-8a and Taylor C (types A and B). The action of the compound of formula (I) to inhibit the growth of other viruses was easily tested in vitro by a spot inhibition test similar to that described in the literature. [Reference: Sinope, Applied Miorobiology 9 (1), 66-92 (1961)] The specific tests used are described in detail in the table below.

[Test Methods]

African green monkey kidney cells (BSC-1) or Hellesef (5-3) were incubated in 5% inactivated bovine fetal serum (FBS) and penicillin (150 units per millimeter) in a 37 ° C falcon flask (25 cc). ) And medium 199 containing streptomycin (150 mcg / ml). When a confluent monolayer is formed, the supernatant is removed from the growth medium and a dilution of 0.3 milliliter of the appropriate virus (Eco, Dengo, Cocksackie, Polio, Nasal virus) is added to each flask. After one hour of absorption at room temperature, the virus-infected cell sheet is covered with 1% of ionic agar No. 21 and 1991 double-strength medium containing FBS, penicillin and streptomycin (where the drug is applied). Is contained at concentrations of 100, 50, 25, 12, 6, 3 and 0 micrograms per milliliter). Flasks containing no drug shall be used for the control test. The thiazolinyl benzimidazole compound of formula (I) is prepared at a concentration of 10 ⁴ mcg / ml in dimethyl sulfoxide. The flask is incubated for 72 hours at 37 ° C. for polio, Coxsackie, Yeko and Mengo viruses and for 120 hours at 32 ° C. for the nasal cold virus. Influenza virus, En Arbor, Maryland B, Massachusetts B, Hong Kong A, Pr-8a and Taylor C (types A, B) are incubated for 72 hours at 37 ° C. using MDCK washes (Madin Darby canine kidney cells). The virus is infected with the cells and spots appear in the reproduced areas. A solution of 10% formalin and 2% sodium acetate is added to each flask to inactivate the virus and fix the cell sheet to the surface of the flask. Peripheral cells are stained with a crystal biolet and the number of virus spots of any size is measured. Spot measurements are compared with controls at each drug concentration. The activity of the test compound is expressed as percent decrement or percent inhibition. Optionally the drug concentration is denoted by I ₅₀ , which uses 50% inhibition of spot formation as a measure of activity.

The test results are indicated by the inhibition of this virus type (I) because polioviruses are easy to grow and matched test results can be obtained. However, the activity of Structural Formula (I) compounds was Koxakki (A 9, A 21, B 5), Echo virus (Strains 1-4), Mengo, Nasal cold virus (Strain 25), Polio (Types I, II, III) And influenza viruses such as En Arbor, Maryland B, Massachusetts B, Hong Kong A, Pr-8a and Taylor C (Type A, B). The results for the various thiazolinyl benzimidazole compounds are shown in Table I below.

TABLE I

1-thiazolinyl benzimidazole compounds are tested for both pure and isomeric mixtures. Both isomers inhibit viral growth and 6-isomers are generally more active than 5-isomers.

The compound of formula (I) can inhibit the growth of various viruses when added to the medium in which the virus grows. The compound of formula (I) is used as an aqueous solution and preferably contains a surfactant that removes contamination on the surface of polio, cocksuckie, nasal cold virus, and influenza virus, and is used for glassware, hospital surgery, and food manufacturing facilities of hospitals. Can be used for

Moreover, the compound may be administered orally at 1 to 300 milligrams per kilogram of body weight to warm-blooded animals and humans. This administration can be repeated periodically if necessary. According to general administration, the antiviral compound may be administered every four to six hours.

Preferably, the compound of formula (I) may be appropriately administered as a suppository. For oral administration, the compound may be a pharmaceutical diluent such as lactose, sucrose, starch, cellulose, talc, stearic acid, magnesium, magnesium oxide, calcium sulfate, acacia powder, gelatin, sodium alginate, sodium benzoate, stearic acid or A carrier can be added and each composition can be a tablet or a capsule. The compound can also be administered parenterally. The present compounds can also be mixed with liquids to administer non-dropping agents or non-spraying agents.

The following examples illustrate the preparation of starting materials, intermediates and compounds of formula (I).

Example 1

1- (thiazolin-2-yl) -2-amino-5 (6) substituted-benzimidazole (general method)

Five millimoles (140 milligrams) of sodium hydride suspended in mineral oil at 50% are washed three times with n-pentane and decanted. The washed sodium hydride is suspended with 5 milliliters of dimethylformamide under dry conditions. 5 mmol 2-amino-5 (6) -substituted-benzimidazole is dissolved in 25 milliliters of dimethoxyethane (glyme) or a mixture of glyme and dimethylformamide (DMF) (15: 1 ratio) It is added dropwise while stirring to the suspension. Stirring is continued for several hours at room temperature until practically completely anions are formed. 5 mmol (605 mg) of chloroethyl isothiocyanate dissolved in dimethylform amide is added dropwise to the anion solution, followed by stirring overnight. The residue is taken up in ethyl acetate and filtered. The ethyl acetate filtrate is washed with water and dried. The 1- (thiazolin-2-yl) -2-amino-5 (6) -substituted-benzimidazole product is obtained by evaporating or concentrating the solvent. This product is purified by recrystallization with a suitable solvent such as ethyl acetate, chloroform, methanol or mixtures thereof.

The following compounds are prepared according to the above method from 2-aminobenzimidazoles substituted at the 5 (6) -position with the appropriate benzoyl group. 1- (thiazolin-2-yl) 2-amino-5 (6) -benzoylbenzimidazole2-amino-5 (6) -benzoylbenzimidazole 0.4 grams (27 mmoles) to 680 milligrams (8.3%) Obtained.

Assay: C ₁₇ H ₁₅ N ₄ OS Molecular Weight 323

Calculated Value: C 63.34, H 4.38, N 17.38, S 9.93

Found: C 63.14, H 4.19, N 17.08, S 9.72

Example 1A

Repeating the procedure of Example 1 using the bases and solvents listed in the following table gives the compound 1- (thiazolin-2-yl) -2-amino-6-benzoylbenz imidazole of Example 1 It is obtained in the same yield.

[table]

Example 2

300 grams of 4-aminobenzophenone (1.52 mol) is added to a small amount of a stirring solution in which 250 milliliters of acetic anhydride is dissolved in 250 milliliters of benzene. The temperature of the mixture is raised to about 70 ° C. The reaction mixture is stirred overnight. The precipitated product is filtered off, washed with benzene and dried. The yield of 4-acetamido benzophenone is 333.8 grams (91.5%) and has a melting point of 150 to 152 占 폚 (melting point of 155 占 폚, Chem. Abst. 55, 18651).

23 grams (0.1 mol) of 4-acetamido benzophenone, 50 milliliters of acetic anhydride and 20 milliliters of acetic acid are stirred together. A solution of 15 milliliters of 90% nitric acid, 10 milliliters of acetic acid and 0.2 grams of urea is slowly added to the benzophenone mixture. The reaction mixture is maintained at about 50 ° C. during nitration. When the mixture is stirred and cooled to ambient temperature, the mixture becomes very dense. Pour this dense slurry on ice to form an insoluble product which is filtered to yield 17.7 grams (62.5% yield) of 4-acetamido-3-nitro benzophenone.

Assay: C ₁₅ H ₁₂ N ₂ O ₄ Molecular weight 284.27

Calculated Value: C 63.38, H 4.26, N 9.85, O 22.51

Found: C 63.57, H 4.03, N 9.90, O 22.27

10 grams of 4-acetoamido-3-nitrobenzophenone is added in small portions to 40 milliliters of sulfuric acid. The reaction temperature is suitably adjusted with a thermostat. After stirring for 45 minutes, the reaction mixture is carefully poured on ice. The precipitated product is filtered to afford 4-amino-3-nitro benzophenone.

Assay: C ₁₃ H ₁₀ N ₂ O ₃ Molecular weight 243.23

Calculated Value: C 64.16, H 4.16, N 11.56, O 19.81

Found: C 64.19, H 4.00, N 11.37, O 19.72

50 grams of 4-amino-3-nitrobenzophenone are hydrogenated at 2.74 × 10 ⁶ dyne / cm 2 using 945 milliliters of tetrahydrofuran and 15 grams of Ranickel at room temperature. After 4 hours, 3 equivalents of hydrogen are absorbed. The catalyst is filtered off and the filtrate is evaporated in vacuo to give a solid residue. This residue is chromatographed on silica gel using ethyl acetate as eluent.

Combining 5 to 9 in fractions yields 43.6 grams (3% yield) of 3,4-diamino benzophenone. 0.2 mol (542.4 grams) of 3,4-diaminobenzophenone is dissolved in 100 milliliters of methanol and mixed in 1 liter of water. 0.2 mole (21.8 grams) of cyanogen bromide is slowly added to the mixture with stirring. Form a reaction overnight. The reaction mixture is filtered and the filtrate is neutralized with ammonium hydroxide (pH = 7.00). The precipitated product was collected, washed with water and dried in a vacuum oven to give 31 grams (68.5%) of 2-amino-5 (6) -benzoyl benzimidazole.

Assay: C ₁₄ H ₁₁ N ₃ O Molecular weight: 237.2

Calculated Value: C 70.87, H 4.67, N 17.71

Found: C 70.88, H 4.60, N 17.48

When 2-amino-5 (6) -benzoylbenzimidazole is reacted according to the preparation of Example 1, 1- (thiazolin-2-yl) -2-amino-5 (6) -benzoyl benzimidazole is obtained. This is consistent with the product of Example 1.

Example 3

5 mmol (1.61 grams) of 1- (thiazolin-2-yl) -2-amino-5 (6) -benzoylbenz imidazole, 1.0 gram of hydroxylamine hydrochloride and 200 milliliters of methanol are heated to reflux for 12 hours. . The reaction mixture is evaporated in a steam bath and concentrated to about half of the original amount. Dilute the mixture with 100 milliliters of buffer (pH = 7.00). The precipitated product was collected to give 650 mg (40%) of 1- (thiazolin-2-yl) -2-amino-5 (6)-(α-hydroxyiminobenzyl) -benzoimidazole.

Assay: C ₁₆ H ₁₅ N ₅ OS Molecular Weight 325

Calculated Value: C 60.52, H 4.48, N 20.76

Found: C 60.13, H 4.40, N 20.37

Example 4

5 mmol (1.61 grams) of 1- (thiazolin-2-yl) -2-amino-5 (6) -benzoylbenzimidazole, 1.0 gram of hydroxylamine hydrochloride and 200 milliliters of methanol are heated to reflux for 12 hours. . The reaction mixture is evaporated in a steam bath and concentrated to about half of the original amount. Dilute the mixture with 100 milliliters of buffer (pH = 7.00). The precipitated product is collected to give 1- (thiazolin-2-yl) -2-amino-5 (6)-(α-hydroxyiminobenzyl) -benzoimidazole 650 milligrams (40%).

Example 5

(A) 4-amino-3-nitrobenzyl alcohol

50 grams (0.27 mol) of 4-chloro-3-nitrobenzyl alcohol, 250 milliliters of methanol and 200 milliliters of ammonia water are placed in a cooled autoclave. Block the autoclave and heat to 150 ° C. After cooling the volatile components are removed by evaporation in the autoclave.

The residue is taken up in ether, the precipitated ammonium chloride is filtered off and the ether filtrate is evaporated in vacuo to give a solid residue. The product was recrystallized from anhydrous alcohol / ethyl acetate to give 23.6 grams (52% yield) of 4-amino-3-nitrobenzyl alcohol. Melting Point: 100-101 ° C

Assay: C ₇ H ₈ N ₂ O ₃ Molecular weight 168

Calculated Value: C 50.00, H 4.80, N 16.66

Found: C 49.72, H 4.56, N 16.44

(B) 3,4-diaminobenzyl alcohol

6 grams (0.035 mole) of 4-amino-3-nitrobenzyl alcohol, 95 milliliters of tetrahydrofuran and 0.5 grams of rannickel were hydrogenated at 2.74 × 10 ⁶ dgne / cm 2 and at room temperature until hydrogen was absorbed. The catalyst is filtered off and the filtrate is evaporated in vacuo to give 4.83 grams (82% yield) of 3,4-diamino benzyl alcohol.

Analytical Value: C ₇ H ₁₀ O ₂ N Molecular Weight 138

Calculated Value: C 60.85, H 7.30, N 20.28

Found: C 60.90, H 7.15, N 19.98

(C) 2-amino-5 (6) -hydroxymethyl benzimidazole

Dissolve 2 grams (0.014 mol) of 3,4-diaminobenzyl alcohol in 40 milliliters of methanol and add 1.6 grams (0.014 mol) of cyanogen bromide to this solution in 10 milliliters of methanol. After standing at room temperature overnight, the reaction mixture is evaporated to dryness in vacuo to afford 3,4-gram (yield 97%) of hydrobromide of 2-amino-5 (6) -methylbenzimidazole.

Optionally, this compound is also obtained from 4-amino-3-nitrobenzyl alcohol without isolating the intermediate after hydrogenation, and the filtrate obtained after removing the hydrogen catalyst is treated with a cyanogen bromide solution dissolved in methanol.

This product is separated as above.

(D) 2-amino-5 (6) -formylbenz imidazole

250 milligrams of 2-amino-5 (6) -hydroxymethyl benzimidazole was suspended in 7 milliliters of acetone, the mixture was cooled in an ice bath and Jones reagent (0.3 milliliters) was added to the cooled reaction mixture and the reaction was added at 0 ° C. Continue for about 5 minutes. The aqueous mixture is extracted with chloroform (40 ml each) and the chloroform extract is washed with water, saturated with sodium chloride and dehydrated.

Chloroform was evaporated in vacuo to give a solid residue and the residue was recrystallized from ethyl acetate to give 57 mg of 2-amino-5 (6) -formyl benzimidazole. N.M.R spectrum shows the correct compound with formyl group.

(E) 1- (thiazolin-2-) yl) -2-amino-5 (6) -formylbenzimidazole

355 milligrams of sodium hydride (7.4 mmol) as a 50% mineral oil suspension is washed three times with n-pentane to remove the mineral oil. The washed sodium hydride is treated with 7 milliliters of dimethylformamide (DMF). A solution of 1.2 grams (7.4 mmol) of 2-amino-5 (6) -formylbenzimidazole in 20 milliliters of DMF was added to a suspended hydrogen compound under anhydrous conditions. The reaction is stirred at room temperature for 3 hours to form anions. A solution of 895 milligrams (7.4 mmoles) of β-chloroethylisothiocyanate in dimethoxyethane (DME) was added to the reaction mixture, the reaction was stirred overnight, and the reaction mixture was evaporated to dryness in vacuo. The insoluble product is filtered and the filtrate is evaporated in vacuo to afford a residue which is then treated with ethyl acetate and the mixture is centrifuged to collect the solids. The solids were combined and stirred for several hours with 50 milliliters of water and the insoluble material was filtered to yield 1.1 grams of 1- (thiazolin-2-yl) -2-amino-5 (6) -formyl benzimidazole.

Assay: C ₁₁ H ₁₀ N ₄ SO molecular weight 242

Calculated Value: C 53.64, H 4.09, N 22.75

Found: C 53.86, H 4.20, N 22.46

Example 6

(A) 4-acetamido acetophenone

100 grams of p-aminoacetophenone is added to 400 milliliters of acetic anhydride in small portions and pyridine is added to maintain a uniform solution. After the reaction mixture was stirred at room temperature for 2 hours, the mixture was poured into 3.5 liters of cold water and the precipitated product was collected to give 108.5 grams (93%) of 4-acetamido acetophenone.

Assay: C ₁₀ H ₁₁ NO ₂ Molecular Weight 177

Calculated Value: C 67.78, H 6.26, N 7.90

Found: C 68.03, H 6.47, N 8.20

(B) 3-nitro-4-acetamido acetophenone

Five grams of 4-acetamido acetophenone are added in small portions to 25 milliliters of red pyrogen nitric acid at 0 ° to 5 ° C. After complete addition the mixture is stirred for 15 minutes and the reaction mixture is carefully poured on ice and the precipitated product collected to yield 4.7 grams (75%) of 3-nitro-4-acetamido acetophenone.

(C) 3-nitro-4-amino acetophenone

Add 16 grams of 3-nitro-4-acetamido acetophenone to 160 milliliters of concentrated sulfuric acid and stir at room temperature for about 1 hour. This mixture is carefully poured into cold water and the precipitated product is filtered to yield 9.5 grams (73%) of 3-nitro-4-amino acetophenone.

Assay: C ₈ H ₈ N ₂ O ₃ Molecular weight 180

Calculated Value: C 53.33, H 4.48, N 15.55

Found: C 53.18, H 4.33, N 15.87

(D) 2-amino-5 (6) -acetyl benzimidazole

4.5 grams of 3-nitro-4-amino acetophenone is hydrogenated at 4.13 × 10 ⁶ dyne / cm 2 using 145 milliliters of 1 gram of ethyl acetate platinum and 3 grams of Laninib at room temperature. Three equivalents of hydrogen are absorbed within 5 hours, the catalyst is filtered off, and then 3 grams of cyanogen bromide is added to the filtrate and the mixture is stirred for 24 hours to precipitate the hydrobromide of the product which is then collected and 2 grams of 2-amino-8 (6) -acetylbenzimidazole hydrobromide is obtained.

Assay: C ₉ H ₉ N ₃ O HBr Molecular Weight 256

Calculated Value: C 42.21, H 3.94, N 16.41

Found: C 42.43, H 4.09, N 16.35

(E) 1- (thiazolin-2-yl) -2-amino-5 (6) -acetyl benzimidazole

Five millimoles (870 milligrams) of 2-amino-5 (6) -acetylbenzimidazole are dissolved in a mixture of 25 milliliters of dimethoxyethane (DME) and 3 milliliters of dimethyl formamide. A solution of keto benzimidazole is added dropwise with stirring to 240 milligrams (5-mmol) of sodium hydride as a 50% mineral oil suspension dissolved in DME under dry conditions. The reaction is continued for about 3 hours until salt formation is complete.

600 milligrams (5 mmol) of β-chloroethyl isothiocyanate is added dropwise and the reaction mixture is stirred overnight at room temperature before the insoluble precipitate is filtered off. The crude product is boiled in a mixture of chloroform and methanol, the insoluble product collected, washed with water and dried.

The yield of 1- (thiazolin-2-yl) -2-amino-5 (6) -acetylbenzimidazole is 300 milligrams (23%).

Assay: C ₁₂ H ₁₂ N ₄ OS Molecular Weight 260

Calculated Value: C 55.37, H 4.65, N 21.52

Found: C 55.15, H 4.72, N 21.36

Example 7

1- (thiazolin-2-yl) -2-amino-5 (6) -propionyl benzimidazole is carried out from 1 gram (5.3 mmol) of 2-amino-5 (6) -propionyl benzimidazole. Prepared in the same manner as in Example 4. 100 mg (6.9%) are obtained, which is recrystallized from a mixture of chloroform and methanol.

Assay: C ₁₃ H ₁₄ N ₄ OS molecular weight 274

Calculated Value: C 56.91, H 5.14, N 20.42

Found: C 56.55, H 5.21, N 20.12

Example 8

1- (thiazolin-2-yl) -2-amino-5 (6) -butyrylbenzimidazole was obtained in 1 gram (4.9 mmol) of 2-amino-5 (6) -butyryl benz as in Example 6. Obtained from imidazole, the yield is 556 milligrams and m / e is 288,245 (m-43 or propyl group).

Example 9

(A) 2-chloro-1-nitro-5-renoylbenzene

To a solution of 50.4 grams (0.25 mol) of 4-chloro-3-nitrobenzoic acid in 500 milliliters of benzene, 35 grams (0.27 mol) of oxalyl chloride in 50 milliliters of benzene are added with stirring. 0.5 milliliter of pyridine is added to the mixture and the mixture is heated and stirred until it is completely in solution. The solvent was removed and the solid was dried in vacuo, then the solid was dissolved in 100 milliliters of methylene chloride, and then 100 milliliters of methylene chloride and 30 grams were dissolved in an ice-alcohol bath and over 45 minutes in a nitrogen atmosphere of 0 to 5 ° C. Add dropwise to the aluminum chloride mixture. To this slurry is added 100 milliliters of methylene chloride and the mixture is left to warm to room temperature for about 1 hour and then heated with water until a complete solution is obtained (about 45 minutes at 35-40 ° C.). When a yellow precipitate begins to form, it is cooled to 0 ° C and added dropwise with stirring a solution of 20 grams (0.24 mole) thiophene in 40 milliliters of methylene chloride to this solution at -5 ° C to 0 ° C. Heating overnight at room temperature gives a yellow solution which is poured onto ice. The crude compound was extracted with methylene chloride and the organic layer was washed and dehydrated with potassium hydrogen carbonate solution, concentrated in vacuo, dissolved in benzene, treated with carbon, filtered and concentrated to dryness to 49.5 grams (74%) of 2-chloro-1. Nitro-5-tenoylbenzene is obtained as a brown solid.

(B) 2-nitro-4-tenoylaniline

16 grams (0.06 mole) of the compound was aminated with a solution of 3 milliliters of ammonia in 72 milliliters of methanol and 13 milliliters of tetramethylsulfone for 15 hours at 120 ℃. The solvent was removed in vacuo and 150 mL of water was added to the resulting residue, the solution was acidified with 1 mL of hydrochloric acid, filtered and washed with diethyl ether and dried to give 11.4 grams of 2-nitro-4-tenoylaniline. (77%) is obtained.

(C) 2-amino-5 (6) -tenoyl benzimidazole

A solution of 11 grams (0.044 moles) of 2-nitro-4-tenoylaniline in 80 ml of methanol was reduced in a solution of 10 ml of tetrahydrofuran in 1 gram of 5% palladium / carbon at room temperature for 19 hours.

The solution is filtered and 4.7 grams (0.044 moles) of cyanogen bromide is added. The mixture was stirred for 2 hours, concentrated in vacuo, diluted in 200 milliliters of water, filtered and dehydrated with potassium carbonate to afford 6 grams (56%) of 2-amino-5 (6) -tenoyl-benzimidazole. .

(D) 1- (thiazolin-2-yl) -2-amino-5 (6) -tenoylbenzimidazole

5 grams (0.02 mol) of 2-amino-5 (6) -tenoylbenzimidazole was reacted according to the method of Example 1, and 3 grams (45%) of 2- (thiazolin-2-yl) -2- Amino-5 (6) -tenoyl benzimidazole is obtained. m / e 328.

Example 10

1 gram (0.003 mole) of 1- (thiazolin-2-yl) -2-amino-5 (6) -tenoyl benzimidazole (prepared by Example 9), 1.0-gram of hydroxylamine Hydrochloride and 50 milliliters of methanol are heated to reflux for about 12 hours. The reaction mixture is concentrated in vacuo and the methanol is dissolved again and then 50 milliliters of buffer (pH = 7.00) and 50 milliliters of water are added.

The precipitated product is collected to yield 700 milligrams (68%) of 1- (thiazolin-2-yl) -2-amino-5 (6)-(α-hydroxyimino thienylmethyl) benzimidazole. m / e 343.

Example 11

137 mg of 1- (thiazolin-2-yl) -2-amino-5 (6) -propionyl benzimidazole (in accordance with the method of Example 7) in 100 mg of hydroxylamine hydrochloride and 20 milliliters of methanol Prepared) was reacted according to the method of Example 3 to obtain 55 mg of 1- (thiazolin-2-yl) -2-amino-5 (6)-(α-hydroxyiminopropyl) benzimidazole. To obtain. m / e 289.

Example 12

1.1 grams (0.005 moles) of carboxyketoxyl in a solution of 1.6 grams (0.005 moles) of 1- (thiazolin-2-yl) -2-amino-5 (6) -benzoylbenzimidazole in 200 milliliters of methanol Add amine hemihydrochloride and 0.3 milliliter (0.003 mole) of concentrated hydrochloric acid to reflux for 16 hours. The mixture is concentrated in vacuo to 1/4 the initial volume, diluted with 100 milliliters of water and 200 milliliters of buffer (pH = 10.00) and stirred.

The precipitate formed was filtered and recrystallized with ethyl acetate to give 0.6 grams of 1- (thiazolin-2-yl) -2-amino-5 (6)-(α-methoxycarbonyl-methoxyiminobenzyl) benzimidazole. To obtain.

Assay: C ₂₀ H ₁₉ N ₅ O ₃ S Molecular weight 409

Calculated Value: C 58.81, H 4.44, N 17.15

Found: C 59.04, H 4.39, N 17.07

The pH of the filtrate was adjusted to 4 and 0.9 grams of secondary precipitate was isolated as above and 1- (thiazolin-2-yl) -2-amino-5 (6)-(α-hydroxycarbonylmethoxy-imino Benzyl) benzimidazole is obtained.

Assay: C ₁₉ H ₁₇ N ₅ O ₃ S.H ₂ O Molecular weight 413

Calculated Value: C 55.34, H 4.37, N 16.99

Found: C 55.48, H 3.93, N 16.54

Example 13

A solution of 274 milligrams of 1- (thiazolin-2-yl) -2-amino-5 (6) -propionyl benzimidazole (prepared in Example 7) was 200 milligrams of thiosemicarbazide, 1.0 milliliter Hydrochloric acid and 40 milliliters of methanol are added. The mixture was treated according to Example 4 to yield 169 mg of 1- (thiazolin-2-yl) -2-amino-5 (6)-(α-thiocarbamyl hydrazonopropyl) benzimidazole. m / e 347.

Claims (1)

The following compound of formula (II) is reacted with haloethyl isothiocyanate of formula (IV) in the presence of a base and a solvent to obtain the following compound of formula (I) wherein R is hydrogen and Z is oxygen, and then the resulting compound is substituted. Optionally reacted with an amine or thiosemicarbazide, wherein Z is hydroxyimino, thiocarbamyl hydrazone, α-methoxycarbonylmethoxyimino, or α-hydroxycarbonyl methoxyamino To obtain a thiazolinyl keto benzimidazole compound of formula (I):

Wherein R is hydrogen, R ₁ is alkyl, thienyl or phenyl having 1 to 3 carbon atoms, Z is hydroxyimino, α-methoxycarbonylmethoxy imino, α-hydroxy carbonylmethoxy imino or thio Carbamylhydrazono,

Is at position 5 or 6, m is 1, Z 'is oxygen and X is chloro or bromo.