KR800001220B1 - Process for thiazolinil ketobenzimidazole - Google Patents

Abstract

Title comps. (I; R=H, R1=1,3-dithioran-2-yl or 1-(C1-3 alkyl)-tetrazol-5-yl) useful as virucides, were prepd. by reaction of comp. II and haloethiocyante (III; X=Cl, Br) in the presence of a base. Thus, a suspended soln. of 240 mg NaH in 5ml dimethoxyethane was added in a soln. of 1.. 19g 2-amino-5(6)-(1, 3-dithioran-2-yl)benzimidazole in 100 ml dimethoxyethane, and stirred for 45 min, followed by addition of a soln. contg. 605mg chloroethyliocyanate in dimethoxyethane, stirred for 16 hr to give I.

Description

Method for preparing thiazolinyl ketobenzimidazole 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.

Wherein R is hydrogen, R ₁ is 1,3-dithioran-2-yl or 1- (alkyl having 1 to 3 carbon atoms) -tetrazol-5-yl, R ₁ is at the 5 or 6 position, 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 in the UK (Lyrell and Byron, Lancet 1,76,1966) indicates that 74% of people with colds have the cold-cold virus. Since more than 80 nasal cold viruses are known, the development of substantial nasal cold virus waxes is not easy and therefore 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-thiazolinylbenzimidazol-2-ones having anti-inflammatory action.

Derwent, 26199 W / 16 discloses 1-thiazolinyl-2-phenylbenzimidazole 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.

In the preparation method of the present invention, the following structural formula (II) is added to the base and the following structural formula in the presence of a base such as sodium hydride, sodium methoxide, or potassium t-butoxide, and a solvent such as dimethoxyethane, tetrahydrofuran or toluene. Reaction with halo ethylisothiocyanate of IV) to give a compound of formula (I).

R ₁ in the above formula is as described above and 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. will be.

Compounds useful in the preparation of the present invention include salts (III) of the tautomeric benzimidazole compounds represented by the following formula (II) with haloethyl isothiocyanates of the formula (IV), i.e., X- (CH ₂ ) _2- NCS (optionally substituted on the carbon chain with a methyl group, wherein R ₁ is as described above and X is chloro or bromo) to react with a compound of formula (V) wherein R is hydrogen and R ₁ is 1- ( Prepared by obtaining the above compound of formula (I) which is Ci_ ₃ alkyl) -tetrazol-5-yl or 1,3-ditian-2-yl.

The term “tautomer benzimidazole” relates to a benzimidazole compound of formula (II) in which a nitrogen atom can be substituted with a hydrogen atom. Benzimidazole reactants having a substituent of R ₁ at the 5 position of the benzene moiety unsubstituted with the nitrogen atom have the corresponding tautomers, which are in equilibrium where the substituents are optionally present at the 6 position. 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 designated as 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 “thiazolinyl” or “thiazolin-2-yl” relates to the N ₁ moiety of formula (I), which refers to the 4,5-dihydro thiazole group attached at position 2, which is 4- and / or It may also have a methyl substituent in the 5-position.

Benzimidazole anion (III) reacts with aliphatic haloethyliso thiocyanate (IV) to form a thiourea intermediate in situ, which is intramolecular alkylated on a sulfur atom to form 1-thiazolinyl benzimide of formula (V). Produces a dazole. The molar ratio of benzimidazole reactant (II) to haloethyliso thiocyanate (IV) is from 1: 1 to 1: 1.5 and the reaction time takes from 1 to 24 hours at temperatures between 25 ° and 150 ° C. Methods and conditions for preparing 1-thiazolinyl benz imidazole 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 the tautomer anions (III) with halo ethylisothiocyanates generally provides a 1: 1 mixture of 5 (6) -isomers of the thiazolinyl benzimazole 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).

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 benz imidazole compound is prepared first 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.

Other necessary benzimidazole reactants are prepared by phenyl ring 0-phenylenediamine substituted with 1- (alkyl having 1 to 3 carbon atoms) -tetrazol-5-yl. 2-Aminobenzimidazole compounds are prepared by ring-cloning 0-phenylenediamine with cyanorene bromide according to the method of Boot et al. [Biol. Chem. J. 32, 1101 (1938)] Various preparations of benz imidazole have also been published in the literature. Viceburger, “The Chemistry of Heterocyclic Compounds Imidazole and Its Derivatives” (Interscience Publisher Co ,. New York, 1953)

The haloethylisothiocyanate reactant of formula (IV) optionally substituted with a methyl group can be prepared from its corresponding haloalkylamine (IV) and thiophosgene.

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

Compounds of formula (I) have a wide range of antiviral actions. The compound of the present invention is effective in suppressing the growth of the echovirus Menko, Koxakki (A 9, 21, B 5) polio (type I, II, III) and nasal cold virus (strain 25), as well as En Arbor, Maryland. It also has inhibitory effects against various types of influenza viruses such as B, Massachusetts B, Hong Kong A, Pr-8a and Railer 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. See Sinov, Applied Microbiology 9 (1), 66-92 (1961). Specific tests used are described in detail in the table below.

[Test Methods]

African green monkey kidney cells (BSC-1) or HeLa cells (5-3) were incubated in 5% inactivated bovine rat serum (FBS), 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 milliliters of the appropriate virus (eco, mengo, cocksuckie, polio, nasal cold virus) is added to each flask. After incubation for 1 hour at room temperature, the virus infected cell sheets are covered with 1% ionic agar No. 21 parts and 199,1 parts of medium having twice the strength containing FBS, penicillin and streptomycin. (The drug 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 flasks are incubated for 72 hours at 37 ° C. for polio, Coxsackie, Echo and Mengo virus and for 120 hours at 32 ° C. for nasal cold virus. Influenza virus, Ann 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 cells (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 represented 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 the compounds of structural formula (I) was found to be coxsackies (A9, A21, B5), echoviruses (strains 1-4), mengo, nasal cold virus (strain 25), polio (types I, II, III) and influenza viruses. Virus media such as, for example, En Arbor, Maryland B, Massachusetts B, Hong Kong A, Pr-8a, and Taylor C (types A, B) were identified. 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 which removes contamination on the surface of polio, cocksuckie, nasal cold virus, and influenza virus. Can be used for

Furthermore, the compound may be administered orally in the range of 1 to 300 milligrams per kilogram of body weight for warm-blooded animals and humans. This administration can be repeated periodically if necessary. According to general administration, the antiviral compound may be administered every 4 to 6 hours.

Preferably, the compound of formula (I) may be appropriately administered as a suppository. For oral administration, the compound is a pharmaceutical diluent or carrier such as lactose, sucrose, starch, cellulose, talc, magnesium stearate, magnesium oxide, calcium sulfate, acacia powder, gelatin, sodium alginate, sodium benzoate, stearic acid May be added, and each composition may be a tablet or 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 dimethylform amide under dry conditions. 5 mmol 2-amino-5 (6) -substituted benzimidazoles are dissolved in 25 milliliters of dimethoxyethane (glyme) or a mixture of glyme and dimethylformamide (DMF) (15: 1 ratio) in basic suspension It is added dropwise with stirring. Stirring is continued for several hours at room temperature until practically completely anions are formed. 5 mmol (605 mg) of chloroethyl isothiocyanate dissolved in dimethylformamide is added dropwise to the anion solution and the stirring is continued overnight. The residue is taken up in ethyl acetate and filtered. The ethyl acetate filtrate is washed with water and dried. The 1- (riazolin-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- (riazolin-2-yl) -2-amino-5 (6) -benzoyl benzimidazole 2-amino-5 (6) -benzoyl benzimidazole 0.4 gram (27 mmol) to 680 mg (8.3%) Is obtained.

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

Calculated Value: C63.34, H4.38, N17.38, S9.93

Found: C63.14, H4.19, N17.08, S9.72

Melting points of the 5-isomers are 225-226 ° C., and melting points of the 6-isomers are 232-234 ° C.

Example 1A

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

Example 2

For 4-amino-benzofe, 300 grams (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-acetamidobenzophenone is 333.8 grams (91.5%), and the melting point is 150 to 152 ° C (melting point 155 ° C in literature, Chem. Abst. 55, 18651).

23 grams (0.1 mol) of 4-acetamidobenzofe stirs 50 milliliters of acetic anhydride and 20 milliliters of acetic acid 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. This thick slurry is poured onto ice to form an insoluble product which is filtered to yield 17.7 grams (62.5% yield) of 4-acetamido-3-nitrobenzophenone.

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. Adjust the reaction temperature to constant temperature. After stirring for 45 minutes, the reaction mixture is carefully poured on ice. The precipitated product is filtered to afford 4-amino-3-nitrobenzophenone.

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 111.37, O 19.72

50 grams of 4-amino-3-trobenzophenone 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 (42.4 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. Let the reaction proceed 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

Reaction of 2-2-amino-5 (6) -benzoylbenzimidazole according to the method of Example 1 affords 1- (thiazolin 2-yl) -2-amino-5 (6) -benzoylbenzimidazole Which is consistent with the product of Example 1.

Example 3

240 milligrams (5 mmol) of a solution of 1.19 grams (5 mmol) of 2-amino-5 (6)-(1,3-dithiolin-2-yl) benzimidazole in 100 milliliters of dimethoxyethane A solution of sodium hydride (50% mineral oil) suspended in 5 milliliters of dimethoxy ethane is added. The yellow solution is stirred for 45 minutes at room temperature, a solution of 605 mg (5 mmol) of chloroethylisothiocyanate in dimethoxyethane is added, the solution is stirred overnight (16 hours), filtered and evaporated to dryness. The residue is taken up in methanol-methylene chloride and chromatographed with ethyl acetate on 60 grams of Woelm silica gel. The desired fractions are collected, washed twice with dimethyl ether and dried to obtain 78 mg of 1- (thiazolin-2-yl) -2-amino_5 (6)-(1,3-dithiolan-2-yl) benz Obtain imidazole.

Example 4

A solution of 10.3 grams (0.05 mol) of 3-nitro-4-acetamidobenzonitrile, 3.5 grams of sodium azide and 3.9 grams of ammonium chloride in 100 milliliters of dimethylformamide was refluxed for 16 hours. The cooled reaction mixture was poured into 500 milliliters of 1N hydrochloric acid, diluted with 300 milliliters of water, and the precipitated yellow product was collected to obtain 10 grams (81%) of 5- (3-nitro-4-acetamidophenyl) tetrazole. To obtain. Melting point 210 to 213 ° C (decomposition)

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

31.7 grams (0.13 mol) of 5- (3-nitro-4-acetamidophenyl) tetrazole is dissolved in 200 milliliters of acetone and 23 milliliters (0.17 mol) of triethylamine are added to the reaction mixture. The mixture is stirred until homogeneous, 30 milliliters of methyl iodide is added and after 12 hours, 20 milliliters of methyl iodide is added at room temperature. The precipitated product was collected and the filtrate was concentrated in vacuo to the first quarter to yield 20 grams (59%) of an isomeric mixture of 1 (2) -methyl-5- (3-nitro-4-acetaminophenyl) tetrazole. do.

Assay: C ₁₀ H ₁₀ N ₆ O ₂ Molecular weight 262

Calculated Value: C 45.80, H 3.84, N 32.05

Found: C 45.64, H 3.84, N 32.18

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

Three grams of 1 (2) -methyl-5- (3-nitro-4-acetaminophenyl) tetazole are added to 20 milliliters of concentrated sulfuric acid at room temperature. Tetrazole is slowly added to the solution and the mixture is stirred for 2 hours before the acid mixture is carefully poured into 200 milliliters of cold water. The precipitated product was collected to yield 1.6 grams (95%) of 1 (2) -methyl-5- (3-nitro-4-amino) tetrazole. Melting Point: about 200 ℃

Assay: C ₈ H ₈ N ₆ O ₂ Molecular weight 220

Calculated Value: C 43.64, H 3.66, N 38.17

Found: C 43.37, H 3.70, N 37.89

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

14 grams of 1 (2) -methyl-5- (3-nitro-4-aminophenyl) tetrazole in a solution of 1,3 grams of palladium / carbon in 135 milliliters of ethyl acetate and 350 milliliters of dry alcohol Hydrogenate at ⁶ dyne / cm 2. After 2 hours, 3 equivalents of hydrogen are absorbed. The catalyst was filtered off and the filtrate was evaporated in vacuo to yield 12 grams (98%) of 1 (2) -methyl-5- (3,4-diaminophenyl) tetazole.

Assay: C ₈ H ₁₀ N ₆ Molecular weight 190

Calculated Value: C 50.52, H 5.30, N 44.18

Found: C 50.79, H 5.57, N 43.95

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

5.7 grams (0.03 moles) of 1 (2) -methyl-5- (3,4-diaminophenyl) tetrazole containing 3.2 grams (0.03 mole) of cyanogen bromide in 300 milliliters of water and 30 milliliters of methanol Is added to the slurry. The mixture is stirred for 12 hours, filtered and the filtrate is neutralized with potassium carbonate. The precipitated product was collected to give 5.7 grams (88%) of 1 (2) -methyl-5- (2 aminobenzimidazol-5 (6) -yl) tetrazole.

Assay: C ₉ H ₉ N ₇ Molecular Weight 215

Calculated Value: C 50.23, H 4.22, N 45.56

Found: C 49.56, H 4.34, N 44.06

(F) 1- (thiazolin-2-yl) -2-amino-5 (6)-[1- (2) -methyl-tetrazol-5-yl] benzimidazole

1 equivalent of 1 (2) -methyl-5- (2-aminobenzimidazol-5 (6) -yl) tetrazole was reacted according to the method of Example 1 according to the method of 1- (thiazolin-2-yl) -2 To -amino-5 (6)-[1 (2) -methyltetrazol-5-yl] benzimidazole. Melting Point: 243 ~ 248 ℃ (Decomposition)

Analysis: C ₁₂ H ₁₂ N ₈ S Molecular weight: 300 m / e: 300

Calculated Value: C 48.00, H 4.00, N 37.33

Found: C 47.42, H 4.30, N 37.41

Claims (1)

A process for preparing a thiazolinyl ketobenzimidazole compound of formula (I), characterized by reacting another compound of formula (II) with haloethyl isothiocyanate of formula (IV) in the presence of a base and a solvent.

Wherein R is hydrogen, R ₁ is 1,3-dithioran-2-yl, or 1- (alkyl having 1 to 3 carbon atoms) -tetrazol-5-yl, and R ₁ is at the 5 or 6 position; X is chloro or bromo.