KR810001818B1 - Process for preparing 1-sulfonyl-5(6)-substituted benzimidazoles - Google Patents

Abstract

Sulfonylbenzimidazoles [I; R = C1-4 alkyl, C5-7 cycloalkyl, -NR3R4(R3,R4 = C1-3 alkyl); R1 = H; R2 = R5C(OH)R6-; R5 = phenyl; R6 = C1-7 alkyl; R2 is positioned on 5 or 6 having a virus growth depressing activity were prepd. by the reaction of comps. II and C1-7 alkyl magnesium halide or C1-7 alkyl litium followed by hydrolysis to give I. Thus, methylmagnesium bromide dissolved in ethylether and THF was added through 1hr to 1-dimethylaminosulfonyl-2-amino-6-benzoylbenzimidazole dissolved in THF and refluxed for 5hr to give amorphous 1-dimethylaminosulfonyl-2-amino-6-(α-hydroxy-α-methylbenzyl)benzimidazole.

Description

Method for preparing 1-sulfonyl-5 (6) -substituted-benzimidazole

The present invention relates to a method for preparing 1-sulfonyl-5 (6) -substituted-benzimidazole of the following general formula (I) having a virus growth inhibitory action.

In the above general formula

R is C ₁ -C ₄ alkyl, C ₅ -C ₇ cycloalkyl, or —NR ₃ R ₄ , wherein R ₃ and R ₄ each independently represent C ₁ -C ₃ alkyl

R ₁ is hydrogen '

R ₂ is; Wherein R ₅ is phenyl; R ₆ is C ₁ -C ₇ alkyl and R ₂ is at the 5 or 6 position.

It is estimated that almost 1 billion patients per year occur in the United States alone. A study in the UK (Tyrell and Bynoe Lancet, 1, 76 1966) found that 74% of patients with colds were infected with rhino virus. Since more than 80 kinds of rhinoviruses have already been identified, practical development of rhinovirus waxin is not possible, and chemical therapy has emerged as a more desirable treatment.

The efficacy of a compound that inhibits viral production can be readily demonstrated by testing for antiviral spots in vivo in a manner similar to that described in Siminoff Applied Microbiolohy 9 (1), 66 (1961).

A 1-dimethylaminosulfonyl-2-aminobenz imidazole compound, which is a type of antifungal agent, is described in US Pat. No. 3, 853, 908.

The compounds of the present invention inhibit the growth of viruses, in particular rhinoviruses, polioviruses, coxseviruses, echoviruses and mengo viruses.

The following compound of general formula (I) of the present invention is reacted with a C ₁ -C ₇ alkylmagnesium halide or C ₁ -C ₇ alkyl lithium by reacting an autotomic benzimidazole compound of the following general formula (II) Manufacture.

In the general formula, R and R ₅ are the same as above.

Preferred among the compounds of formula (I) are those wherein R is C ₁ -C ₄ alkyl or —NR ₃ R ₄ , wherein R ₃ and R ₄ are each C ₁ -C ₃ alkyl.

The "tomomeric benzimidazole" refers to a benzimidazole reagent in which hydrogen can be substituted for one of two nitrogen atoms. Benzimidazole reagents that are not substituted on the nitrogen and have substituents at the 5-position of the benzene site will have corresponding tautomers with substituents at the 6-position. Such mixtures of isomers can be indicated by indicating the positions of change as 5 (6). The following describes the definitions of various terms used in the present specification.

“C ₁ -C ₄ alkyl” is a C _1-4 straight and branched aliphatic group including methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secondary-butyl and tert-butyl. C ₁ -C ₄ alkyl includes “C ₁ -C ₃ alkyl”. ＂C ₁ -C ₇ alkyl＂ is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secondary-butyl, pentyl, hexyl, isohexyl, heptyl, isoheptyl, 2,4-dimethyl-3-pentyl, C1-C7 linear and branched aliphatic groups containing t-butyl and neopentyl are shown.

＂C ₃ -C ₇ cycloalkyl＂ has 3 to 7 carbon atoms such as cyclopropyl, methylcyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1-, 2-, 3- or 4-methylcyclohexyl and cycloheptyl A saturated alicyclic ring is shown.

Suitable Grignard reagents for this process are C ₁ -C ₇ alkyl magnesium halides. The C ₁ -C ₇ alkyl lithium reagent produces a product similar to the Grignard reagent. Preferred solvents for the alkylation process include inert organic solvents such as tetrahydrofuran; Or aromatic solvents such as toluene; Ethers such as diethyl ether and the like. Typically used temperature range is 25 ℃ to reflux temperature of the solvent.

Compounds of the general formula (II) as starting materials are described in pending US patent applications 608,415.

The product of this reaction is a 1-sulfonylbenzimidazole compound which is separated by filtration of the reaction mixture and crystallization by concentration of the filtrate. Alternatively the reaction mixture is evaporated to dryness and the residue treated with acetone or methane such as a suitable solvent to crystallize the product or evaporate to give a secondary residue which is dissolved in, for example, methanol. Sulfonylbenzimidazole compounds are recovered from methanol by crystallization.

5 (6) -isomers can be separated by fractional crystallization or column chromatography. Typically the 6-isomer is first crystallized from a solution of the mixture.

The following examples illustrate in more detail the preparation of compounds of formula (I). ＂M / e＂, used in the characterization of the product nothing, is the ratio of mass to charge of ions and appears in the mass spectral spectrum of the product. Typically this value corresponds to the molecular weight of the peak.

Example 1

1-diethylaminosulfonyl-2-amino-6-benzoyl benzimidazole 4.1 in 180 ml of tetrahydrofuran under nitrogen in a solution of 600 ml of tetrahydrofuran and 21.7 ml (60 mmol) of methyl magnesium bromide in diethyl ether. A solution of g (12 mmol) was added dropwise for 1 hour. The compound was refluxed for 5 hours, poured into ice and 1N hydrochloric acid, extracted twice with diethyl ether, washed with saturated sodium chloride, dehydrated and filtered to give an amorphous solid, 1-dimethylaminosulfonyl-2-amino-6- ( 2.9 g of α-hydroxy-α-methylbenzyl) benzimidazole are obtained.

m / e 360.

Elemental Analysis C ₁₇ H ₂₀ N ₄ O ₃ S Mw 360

Calc .: C 56.67; H 5.59; N 15.54.

Found: 56.77 5.46 15.27

Example 2

100 ml of tetrahydrofuran and 22.2 ml (60 mmol) of ethyl magnesium bromide in diethyl ether (2.7 mmol / ml) and 4.1 g of 1-diethylaminosulfonyl-2-amino-6-benzoyl benzimidazole The procedure of Example 1 was repeated to give 3.2 g of 1-dimethyl-aminosulfonyl-2-amino-6- (α-hydroxy-α-hydroxybenzyl) benzimidazole in the form of bubbles. Analysis of C ₁₈ H ₂₂ N ₄ O ₃ S by High Resolution Mass Spectrometer.

Calculated value: 374. 14123

Found: 374. 141

Example 3

A solution of 4.1 g (12 mmol) of 1-diethylaminosulfonyl-2-amino-6-benzoyl benzimidazole in 180 ml of tetrahydrofuran, 100 ml of tetrahydrofuran and 28.6 ml of isopropyl magnesium chloride in 100 ml of tetrahydrofuran ( Repeat the procedure of Example 1 using a solution of 60 mmol) to dissolve 4.0 g of 1-dimethylaminosulfonyl-2-amino-6- (α-hydroxy-α-hydroxybenzyl) benzimidazole in yellow color. Obtained as bubbles.

Yield 65%

Example 4

5.0 g (15) of 1-isopropylsulfonyl-2-amino-6-benzoyl benzimidazole in 200 ml of tetrahydrofuran under nitrogen in a solution of 150 ml of tetrahydrofuran and 31 ml (84 mmol) of methyl magnesium bromide in diethyl ether. Mmol) solution is added dropwise. The mixture is stirred at 25 ° C. for 1 hour, refluxed for 2 hours, cooled, poured into ice and 1N hydrochloric acid, extracted with diethyl ether, 1500 ml of this solution is concentrated to 800 ml, dried and concentrated in vacuo. The product formed is taken up in diethyl ether and diethyl ether / hexane is added to recrystallize from diethyl ether / hexane and the solution is suspended until cloudy. The solution is cooled to 25 ° C., frozen at 10 ° C. and filtered to give 2 g of product. The filtrate is also concentrated in vacuo to recover an additional 2 g of product. The product is 1-isopropyl-2-amino-6- (α-hydroxy-α-methylbenzyl) benzimidazole.

m / e 360, 344 (base)

Elemental Analysis C ₁₈ H ₂₁ N ₃ O ₃ S Mw 359

Calculated Value: C 60.15 H 5.89 N 11.69

Found:

(Primary fraction) C 60.37; H 5.73; N 11.46.

(Secondary spread) 61.30; 6.26; 10.69.

Example 5

The procedure of Example 7 was repeated using 150 ml of tetrahydrofuran, 31 ml (84 mmol) of n-butyl magnesium bromide, 5.0 g (15 mmol) of 1-isopropylsulfonyl-2-amino-6-benzoylbenzimidazole, Reflux for 20 hours yields 5.0 g of 1-isopropyl-sulfonyl-2-amino-6- (α-hydroxy-α-n-butylbenzyl) benzimidazole on a tan foam.

Analysis C ₂₁ H ₂₇ N ₃ O ₃ S Mw 401

Calculated Value: C 62.82 H 6.78 N 10.47

Found: 63.14; 6.57; 10.17

Example 6

The procedure of Example 7 was repeated using 40 ml (85 mmol) of isopropyl magnesium bromide, 5.0 g (15 mmol) of 1-isopropylsulfonyl-2-amino-6-benzoylbenzimidazole, and 200 ml of tetrahydrofuran. 5.0 g of 1-isopropylsulfonyl-2-amino-6- (α-hydroxy-α-isopropylbenzyl) benzimidazole in the form of a foam is obtained. m / e 399.

Example 7

The procedure of Example 7 was repeated using 31 ml of ethyl magnesium bromide (2.7 mmol in diethyl ether), 5 g (15 mmol) of 1-isopropylsulfonyl-2-amino-6-benzoylbenzimidazole and 150 ml of tetrahydrofuran. 4.6 g of 1-isopropylsulfonyl-2-amino-6-(?-Hydroxy-?-Ethylbenzyl) benzimidazole on a beige foam is obtained. m / e 373, 343.

Example 8

Dissolve 30 ml (60 mmol) of n-propyl magnesium bromide in 100 ml of tetrahydrofuran and 4.1 g (5 mmol) of 1-dimethylamino-sulfonyl-2-amino-6-benzoylbenzimidazole in 150 ml of tetrahydrofuran. The procedure of Example 1 was repeated to obtain 3.5 g of 1-dimethylaminosulfonyl-2-amino-6- (α-hydroxy-α-n-propylbenzyl) benzimidazole on a yellowish brown bubble. m / e 388.

Example 9

The procedure of Example 1 was repeated using 80 ml of tetrahydrofuran, 11.1 ml of n-butyl magnesium bromide and 2.05 g of 1-dimethylaminosulfonyl-2-amino-6-benzoylbenzimidazole in 90 ml of tetrahydrofuran. 1.7 g of 1-dimethylaminosulfonyl-2-amino-6-(?-Hydroxy-?-N-butylbenzyl) benzimidazole on a white bubble is obtained. m / e 402.

Example 10

Into a solution of 5 g (13.1 mmol) of 1-cyclohexylsulfonyl-2-amino-6-benzoylbenzimidazole in 200 ml of tetrahydrofuran, 84 ml of ethyllithium was rapidly added dropwise under nitrogen. This reaction is carried out on ice cubes. Once this reaction is complete, allow the solution to warm to 25 ° without removing the ice bath and hold at this temperature for 2.5 hours. The reaction mixture is stirred for 5 hours, diluted with water and then tetrahydrofuran is distilled off under vacuum. The product is extracted twice with chloroform, saturated and filtered to yield 4.1 g of 1-cyclohexylsulfonyl-2-amino-6- (α-hydroxy-α-n-ethylbenzene) imidazole.

Elemental Analysis C ₂₂ H ₂₆ N ₃ O ₃ S

Calculated Value: C 63.90 H 6.58 N 10.16

Found: 64.77; 7.09; 9.38

Compounds of formula (I) exhibit a wide range of antiviral actions, especially the growth of echoviruses, mengo coxki (A ₉ , A ₂₁ , B ₅ ), plio (forms I, II, III) or rhinoviruses (25 species) Not only effective to suppress. It inhibits various forms of influenza viruses, including influenza strains such as Ann Avor, Maryland B, Massachusetts B, Hong Kong A, Pr-8a and Taylor C (forms A, B). The ability of the general formula (I) compounds according to the invention to inhibit other viral growth in vitro is readily determined by the anti-spot test as described in Siminoff, Applied microbiology 9 (1) 66-72 (1961). Prove that.

Detailed test methods are described below, and the compound of formula (I) is tested by the following method.

[Test Methods]

African green monkey kidney cells (BSC-1) or Hela cells (5-3) were placed in batch 199 and deactivated 5% fetal small-size (FBS) penicillin (150 units in 1 ml) and streptomycin 25 cc with (150 mcg / ml) are grown to 37 ° C. in a Falcon flask. Once the fused monolayer has been formed, the growth medium supernatant is removed and a dilution of 0.3 ml of appropriate virus (Eco, Mengo, Coxsekki, Plio or Reno) is added to each flask. After 1 hour of absorption at room temperature, 1% Ionaga 2 (Ionagar NO. 2), double-strength medium 199 and FBS, penicillin and streptomycin consisted of 100, 50, 258, 12, 6, 3 And a medium containing 0 mcg, covering the virus infected cell sheet. Flasks containing no drug shall be used as a control for this test. The stock solution of the sulfonylbenzimidazole compound is prepared by dilution at a concentration of 10 ⁴ mcg / ml in dimethyl sulfoxide. The flasks are incubated for 72 hours at 37 ° C. for Polio, Coxseki, Echo and Mengo virus, and 120 hours at 32 ° C. for Renovirus. A 10% formalin and 2% sodium acetate solution is added to each flask to inactivate the virus and fix the cell sheet to the flask surface. Peripheral cells are stained with crystal violet and virus spots of any size are counted. The scores in each drug involvement are compared to the control scores. The activity of the test compound is expressed as a percentage of reduced spots or as a percentage inhibition. Alternatively, I ₅₀ , a drug concentration that inhibits speckle formation by 50%, can be used as a measure of activity.

The test results indicate inhibition of the virus because Poliovirus Type I is easy to cultivate and results in inconsistent test results. However, general formula (I) compounds include coxeki (A ₉ , A ₂₁ , B ₅ ), echoviruses (1-4 species), menco, rhinoviruses (25 species), and polioviruses (types I, II, III) It has also been found to be active against other viral cultures. Test results for the various sulfonylbenzimidazole compounds are summarized in Table I below, in which the first column represents the number of the above example and the second column is the 5 (6) -position of the corresponding benzimidazole product and the third Row −10 is the percentage of virus spot reduction at drug concentrations between 0.75 and 100 mcg per ml.

* 5 or 6 represents each isomer

The sulfonylbenzimidazole compounds of formula (I) are tested as pure compounds and in isomer mixtures. Both isomers inhibit the growth of the virus and the 6-isomer generally acts stronger than the 5-isomer.

The compound of formula (I) may be orally administered 1-300 mg / kg to warm-blooded animals and the human body. Administration can be repeated periodically as needed. Typically, the antiviral compound can be administered every 4-6 hours.

The compound can be administered as a liquid or nasal spray by mixing with a liquid.

Claims (1)

A method of preparing the sulfonyl benzimidazole compound of the following general formula (I) by reacting a compound of the following general formula (II) with C ₁ -C ₇ alkyl magnesium halide or C ₁ -C ₇ alkyl lithium.

Wherein R is C ₁ -C ₄ alkyl, C ₅ -C ₇ cycloalkyl, or —NR ₃ R ₄ , wherein R ₃ and R ₄ each independently represent C ₁ -C ₃ alkyl R ₁ is hydrogen:

R ₂ is; Wherein R ₅ is phenyl; R ₆ represents C ₁ -C ₇ alkyl.