DK145879B - ANALOGY PROCEDURE FOR THE PREPARATION OF 1-SULPHONYL-5 (6) -SUBSTITUTED BENZIMIDAZOLES - Google Patents

Description

in 145879

The present invention relates to an analogous process for the preparation of novel 1-sulfonyl-5 (6) -substituted benzimidazoles of the general formula I set forth in the preamble of the claim and the process of the invention is characterized by the characterizing part of the claim.

The compounds in question inhibit the growth of viruses.

The incidence of illness in the upper part of the respiratory system is immense. It is estimated that about 10 billion cases occur annually in the United States alone. Studies in England (Tyreli and Bynoe, Lancet 1, 76 (1966)) show that 74% of people with colds were infected with rhinovirus. Since more than 80 strains of rhinovirus have already been identified, development of a practical rhinovirus vaccine is not possible and chemotherapy appears to be a more suitable treatment.

The ability of chemical compounds to suppress the growth of virus in vitro can be readily demonstrated by using a virus stain suppression method analogous to that described by Siminoff in Applied Microbiology, 9 (1), 66 (1961).

U.S. Patent No. 3,853,908 discloses certain antifungal 1-dimethylaminosulfonyl-2-aminobenzimidazole compounds.

From the specification of Danish patent application no. . However, these known benzimidazole derivatives are not as effective as the compounds of the invention.

It is thus the object of the invention to provide a process for the preparation of novel, biologically active benzimidazole compounds which inhibit the growth of viruses, rhinovirus, poliovirus, Coxsackie virus, echovirus and Mengo virus.

The present compounds of formula I are prepared according to the invention by dehydrating intermediates of Formula II. Suitable dehydrating agents in the process of the invention are strong acids such as p-toluenesulfonic acid, sulfuric acid, trifluoroacetic acid, methanesulfonic acid or trifluoromethanesulfonic acid.

The intermediates of formula II are novel compounds which can be obtained by reacting a tautomeric benzimidazole of the general formula c6h5-c - (m 2) (III) acid wherein R is as defined above, with an alkyl magnesium halide having 1-7 carbon atoms or alkyl lithium having 1-7 carbon atoms followed by a hydrolysis. The alkylation is preferably carried out in an inert organic solvent.

The term "tautomeric bezimidazole" refers to benzimidazoles which may be substituted on both ring nitrogen atoms by a hydrogen atom. A benzimidazole which is unsubstituted on the nitrogen atom and which has a 5-substituent group in the benzene ring has a corresponding tautomeric form in which the substituent sits in the 6-position. The isomeric mixture can be indicated by numbering the alternative positions as 5 (6).

Alkyl of 1-4 carbon atoms refers to straight-chain and branched aliphatic radicals of 1-4 carbon atoms comprising methyl, ethyl, butyl, isobutyl, sec-butyl and 3,45879 tert-butyl.

Cycloalkyl of 5-7 carbon atoms refers to saturated alicyclic rings of 5 to 7 carbon atoms such as cyclopentyl, cyclohexyl, 1-, 2-, 3- or 4-methylcyclohexyl and cycloheptyl.

The alkylidene of 1-7 carbon atoms refers to straight and branched chain radicals of 1 to 7 carbon atoms, such as the methylidene, ethylidene, propylidene, isopropylidene, butylidene, isobutylidene, 3-methyl-2-butylidene, 2,4-dimethyl-3-pen -10 thylidene and n-hexylidene.

Preferred solvents for dehydration are aromatic compounds such as benzene and toluene, alkanes such as hexane, and halogenated hydrocarbons such as methylene chloride and chloroform. The temperature is usually between 25 ° C and the boiling point of the solvent.

The benzimidazoles of formula (III) are prepared as described in Danish Patent Application No. 3860/76.

The reaction product is a 1-sulfonylbenzimidazole compound.

This can be isolated by filtration of the reaction mixture and concentration of the filtrate for crystallization. Alternatively, the reaction mixture may be evaporated to dryness and the residue treated with a suitable solvent, such as acetone or methanol, to separate and remove insoluble matter. The solution containing the sulfonylbenzimidazole compound is concentrated to crystallize the product or evaporated to obtain another residue, e.g. dissolved in methanol. The sulfonylbenzimidazole compound is recovered from the methanol by crystallization.

The 5 (6) isomers can be separated by fractional crystallization or by column chromatography. Usually the 6 isomer crystallizes first from a solution of the mixture.

The following examples further illustrate the process for preparing the subject compounds, "m / e" is used to characterize the compounds and refers to the mass charge ratio of ions present in the mass spectrum of the compounds. In general, the values correspond to the molecular weight of the main fractions.

EXAMPLE 1 2 g (5.5 mmol) of 1-dimethylaminosulfonyl-2-amino-6- (α-hydroxy-α-methylbenzyl) benzimidazole in 130 ml of chloroform was reacted with 1.3 g of p-toluenesulfonic acid. The solution was refluxed and stirred for 6 hours. Then the solution was washed with saturated sodium carbonate, dried and filtered to give 1.7 g of 1-dimethylaminosulfonyl-2-amino-6- (α-methylenebenzyl) benzimidazole, mp 201-202 ° C.

Analysis: ^^ 18¾¾8 Molecular Weight 342

Calculated: C, 59.63; H, 5.30; N, 16.36

Found: C, 59.67; H, 5.35; N 16.07 EXAMPLE 2

The procedure of Example 1 was repeated, using 1.2 g (3.21 mmol) of 1-dimethylaminosulfonyl-2-amino-6- (α-ethyl-α-hydroxybenzyl) benzimidazole, 750 mg of p-toluenesulfone and 100 ml of chloroform to give 388 mg of 1-dimethylaminosulfonyl-2-amino-6- (α-ethylidene-benzyl) -benzimidazole, mp: 200-202 ° C (dec).

Mass spectrum of cisH2ON4 ° 2S

Calculated: 356.13107

Found: 356.131 Example 8 When the procedure of Example 1 was repeated using 1.2 g (3 »2 mmol) of 1-dimethylaminosulfonyl-2-amino-6- (oc-isopropyl-α-hydroxybenzyl) benzimidazole, 750 mg p-toluene-sulfonic acid and 100 ml of chloroform were obtained as a beige solid 82 mg of 1-dimethylaminosulfonyl-2-amino-6- (o-iso-propylidenebenzyl) benzimidazole.

Analysis: cigH22N4 ° 2S

Calcd. C, 61.60; H, 5.99; N, 15.12 Pound: C, 61.38; H, 5.81; N 14.85 Example 4 2 g (5.6 mmol) of 1-isopropylsulfonyl-2-amino-6- (α-hydroxy-cc-methylbenzyl) benzimidazole In 100 ml of chloroform, 1.3 g of p-toluenesulfonic acid was reacted. The solution was boiled at reflux and stirred for 4 hours. The solution was cooled to 25 ° C, washed twice with saturated potassium carbonate, washed twice with water, dried over sodium sulfate, concentrated in vacuo and recrystallized from diethyl ether / hexane to give 1.1 g of 1-isopropylsulfonyl-20 2-amino -6- (α-methylenebenzyl) benzimidazole as light orange colored crystals, mp: 147-148 ° Cm / e 341.

Analysis: (^ 18 ^ 19 ^ 3 ^ 2 ^ MV 341

Calculated: C, 63.32; H, 5.61; N, 12.31

Found: C, 63.58; H, 5.53; N 12.15 EXAMPLE 5

The procedure of Example 4 was repeated using 1 g (2.5 mmol) of 1-isopropylsulfonyl-2-amino-6- (α-hydroxy-an-butylbenzyl) benzimidazole, 75 ml of chloroform and 600 mg of p-toluenesulfonic acid, and was refluxed for 90 30 minutes to give 790 mg of 1-isopropylsulfonyl-2-amino-6- (tx-n-butylidene-enzyl) benzimidazole.

Analysis: C ^H ^N ^S MV 383

Calculated: C, 65.77; H, 6.57; N, 10.96

Found: C, 65.49; H, 6.51; N 10.78 m / e 583 (molecular ion), 276 (-SO 2 CH (CH 2) 2).

UV (CH 2 OH):% 212 € 35166; Λ 270 6 17200 EXAMPLE 6

By following the procedure of Example 4 using 890 mg (2.4 mmol) of 1-isopropylsulfonyl-2-amino-6-10 (p-hydroxy-a-ethylbenzyl) benzimidazole, 50 ml of chloroform and 600 mg of p toluene sulfonic acid was obtained as an amorphous foam 630 mg of 1-isopropylsulfonyl-2-amino-6- (oc-ethylidenebenzyl) benzimidazole.

Analysis: c19H2iN3> 02S MV 355

Calculated: C, 64.20; H, 5.96; N, 11.82. Found: C, 63.93; H, 6.04; N 11.64 m / e 355 (molecular ion), 248 (-SO 2 CH (CH 2) 2).

UV (CH 2 OH): 7-212 35000; Λ270 € 17000.

EXAMPLE 7 When the procedure of Example 1 was repeated using 402 mg of 1-dimethylaminosulfonyl-2-amino-6- (α-hydroxy-an-butylbenzyl) benzimidazole in 20 ml of chloroform, 234 mg of p-toluene sulfonic acid and 100 ml of chloroform, 302 mg of 1-dimethylaminosulfonyl-2-amino-6- (a-butylidenebenzyl) benzimidazole were obtained.

EXAMPLE 8 When the procedure described in Example 4 was repeated using 1.0 g of 1-isopropylsulfonyl-2-amino-5- (α-hydroxy-α-isopropylbenzyl) benzimidazole, 75 ml of chloroform and 600 mg of p-toluenesulfonic acid, 850 mg of 1-7 145879 isopropylsulfonyl-2-amino-6- (α-isopropylidenebenzyl) benzimidazole was obtained. m / e 369. UV (CH 2 OH): 2 213 (34700;% 258 £ 14800; £ 280 4400).

EXAMPLE 9 When the procedure described in Example 4 was repeated using 602 mg of 1-dimethylaminosulfonyl-2-amino-6- (α-hydroxy-an-propylbenzyl) benzimidazole, 20 ml of chloroform and 362 mg of p-toluenesulfonic acid, 93 were obtained. mg of 1-dimethylamino sulfonyl-2-amino-6- (α-n-propylidenebenzyl) -benzimidazole.

Analysis: cigH24N4 ° 2S

Calcd. C, 61.60; H, 5.99; N, 15.12

Found: C, 61.53; H 6.14; N 15.01 EXAMPLE 10 To a solution of 3.6 g (8.74 mmol) of 1-cyclohexylsulfonyl-2-amino-6- (α-hydroxy-α-ethyl-benzyl) benzimidazole in 125 ml of chloroform was added. added 2 g of p-toluenesulfonic acid. The reaction mixture was heated to reflux for 6 hours, cooled and left at ambient temperature for 12 hours. The resulting product was washed with saturated sodium carbonate solution, dried over sodium sulfate, filtered and dried to give 5.25 g of 1-cyclohexylsulfonyl-2-amino-6- (a-ethylidene benzyl) benzimidazole as a foam.

Analysis C22H24N3 ° 2S

Calculated: C, 66.81; H, 6.37; N, 10.62. Found: C, 66.58; H, 6.46; N 10.38 8 145879

The present compounds of formula (I) exhibit a broad spectrum of antiviral activity. Not only are they particularly effective in inhibiting the growth of echo virus, Mengo, Coxsackie (A9A, 21.85), polio (type I, II, III) or 5 rhinoviruses (25 strains), but they also inhibit different types of influenza viruses , including influenza strains such as Ann Arbor, Maryland B, Mass Bussets B, Hong Kong A, Pr-8a, and Taylor C (type A, B). The ability of the compounds of this invention to suppress the growth of various viruses in vitro can be readily demonstrated by using the stain reduction test analogous to that described by Siminoff, Applied Microbiology, 9 (1), 66-72 (1961). . The specific experiments are described in detail below. The compounds of this invention were tested according to the following methods:

Porsøgsmetoder

Kidney cells from African monkeys (BSC-1) or Hela cells (5-3) were grown in 25 ml Palcon flasks at 37 ° C in medium 199 with 5% inactivated bovine fetal serum (PBS), penicillin (150 units) , 1 ml) and Streptomycin (150 µg / ml).

Once confluent monolayers were formed, the above growth medium was removed and 0.3 ml of a suitable dilution of virus (echo, Mengo, Coxsackie, polio or rhinovirus) was added to each flask. After absorption for 1 hour at room temperature, the cell layer infected with virus was poured onto a medium containing 1 part 1% Ionagar No. 2 (a purified specific agar marketed by Wilson Diagnostic Company) and 1 part medium 199, a standard medium used in the double strength of normal, with FBS, penicillin and 30 streptomycin containing the active compound at concentrations of 100, 50, 25, 12, 6, 3 and Oyum per. ml.

The flask, which did not contain active compound, served as a control in the experiment. Stock solutions of the sulfonylbenzimide dazole compounds were prepared in dimethyl sulfoxide dilution at a concentration of 10 µg / ml. The flasks were incubated for 72 hours at 37 ° C for polio, Coxsackie, echo and Mengo virus, and for 120 hours at 5 ° C for rhinovirus. Stains could be observed in those areas where viruses were infected and reproduced in the cells.

A solution of 10% formalin and 2% sodium acetate was added to each flask to inactivate the virus and fix the cell layer to the flask surface. The virus spots, regardless of size, were counted after staining the surrounding cells with crystal violet. The stain number was compared to the control sample at each active compound concentration. The effect of the compound in question was expressed as percent stain reduction or percent inhibition.

Alternatively, the concentration that inhibits stain formation 50% can be used as a measure of the effect.

The experiments are expressed as inhibition of Polio virus type I, as this virus is easy to grow and gives consistent results. The effect of the compounds of this invention was confirmed against other viral cultures such as Coxsackie (A9, A21, B5), echo virus (strain 1-4), Mengo, rhinovirus (25 strains) and Polio (type I, II, III). Test results for various sulfone yl benzimidazole compounds are given in Table I below, with column 1 referring to the above examples, while columns 3 - 10 indicate the percentage inhibition at various dilutions of the active compound.

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In order to demonstrate the useful biological effect of the compounds of the present invention in relation to known benzimidazole compounds, the compound 1-dimethylaminosulfonyl-2-amino-6- (α-methylene benzyl) benzimidazole, prepared according to the invention, was compared with the compounds 1-dimethylamide. nosulfonyl-2-amino-6- (hydrazinocarbonyl) benzimidazole and 1-dimethylaminosulfonyl-2-amino-6- (N-ethylcarboxamido) benzimidazole, both known from Danish Patent Application No. 2921/75. The ability of the compounds to suppress the growth of virus in vitro was determined as described above and the results are shown in Table II. It is clear from this table that the compound of the invention is significantly more effective than the comparative compounds.

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The present sulfonylbenzimidazole compounds of formula (i) were tested as pure compounds and as isomeric mixtures. Both isomers inhibit virus growth, however, the 6-isomer is generally more active than the 5-isomer.

The present compounds can be administered orally to warm-blooded mammals, including humans, at doses of 1 -300 mg / kg body weight. The administration may be repeated periodically if necessary. According to general practice, the antiviral compound can be administered every 4 to 6 hours.